You searched for subject:(Virtual Screening).
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Virginia Tech
1.
Lewis, Stephanie N.
Refinement of the Docking Component of Virtual Screening for PPAR.
Degree: PhD, Genetics, Bioinformatics, and Computational Biology, 2013, Virginia Tech
URL: http://hdl.handle.net/10919/23675 
► Exploration of peroxisome proliferator-activated receptor-gamma (PPAR") as a drug target holds applications for treating a wide variety of chronic inflammation-related diseases. Type 2 diabetes (T2D),…
(more)
▼ Exploration of peroxisome proliferator-activated receptor-gamma (PPAR") as a drug target holds applications for treating a wide variety of chronic inflammation-related diseases. Type 2 diabetes (T2D), which is a metabolic disease influenced by chronic inflammation, is quickly reaching epidemic proportions. Although some treatments are available to control T2D, more efficacious compounds with fewer side effects are in great demand. Drugs targeting PPAR" typically are compounds that function as agonists toward this receptor, which means they bind to and activate the protein. Identifying compounds that bind to PPAR" (i.e. binders) using computational docking methods has proven difficult given the large binding cavity of the protein, which yields a large target area and variations in ligand positions within the binding site. We applied a combined computational and experimental concept for characterizing PPAR" and identifying binders. The goal was to establish a time- and cost-effective way to screen a large, diverse compound database potentially containing natural and synthetic compounds for PPAR" agonists that are more efficacious and safer than currently available T2D treatments. The computational molecular modeling methods used include molecular docking, molecular dynamics, steered molecular dynamics, and structure- and ligand-based pharmacophore modeling. Potential binders identified in the computational component funnel into wet-lab experiments to confirm binding, assess activation, and test preclinical efficacy in a mouse model for T2D and other chronic inflammation diseases. The initial process used provided "-eleostearic acid as a compound that ameliorates inflammatory bowel disease in a pre-clinical trial. Incorporating pharmacophore analyses and binding interaction information improved the method for use with a diverse ligand database of thousands of compounds. The adjusted methods showed enrichment for full agonist binder identification. Identifying lead compounds using our method would be an efficient means of addressing the need for alternative T2D treatments.
Advisors/Committee Members: Bevan, David R. (committeechair), Zhang, Liqing (committee member), Bassaganya-Riera, Josep (committee member), Sible, Jill C. (committee member).
Subjects/Keywords: Virtual screening; PPAR
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APA (6th Edition):
Lewis, S. N. (2013). Refinement of the Docking Component of Virtual Screening for PPAR. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/23675
Chicago Manual of Style (16th Edition):
Lewis, Stephanie N. “Refinement of the Docking Component of Virtual Screening for PPAR.” 2013. Doctoral Dissertation, Virginia Tech. Accessed January 19, 2021.
http://hdl.handle.net/10919/23675.
MLA Handbook (7th Edition):
Lewis, Stephanie N. “Refinement of the Docking Component of Virtual Screening for PPAR.” 2013. Web. 19 Jan 2021.
Vancouver:
Lewis SN. Refinement of the Docking Component of Virtual Screening for PPAR. [Internet] [Doctoral dissertation]. Virginia Tech; 2013. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/10919/23675.
Council of Science Editors:
Lewis SN. Refinement of the Docking Component of Virtual Screening for PPAR. [Doctoral Dissertation]. Virginia Tech; 2013. Available from: http://hdl.handle.net/10919/23675
Louisiana State University
2.
Crochet, Robert Blake.
Insights into the Development of Chemotherapeutics Targeting PFKFB Enzymes.
Degree: PhD, 2015, Louisiana State University
URL: etd-11162015-154823
;
https://digitalcommons.lsu.edu/gradschool_dissertations/311
► The PFKFB enzymes control the primary checkpoint in the glycolytic pathway and are implicated in a multitude of diseases: from cancer, to schizophrenia, to diabetes,…
(more)
▼ The PFKFB enzymes control the primary checkpoint in the glycolytic pathway and are implicated in a multitude of diseases: from cancer, to schizophrenia, to diabetes, and heart disease. The inducible isoform, PFKFB3, is known to be associated with the upregulation of glycolysis in many cancers. The first study within this work investigates the potential for using tier-based approaches of virtual screening to target small molecule kinases, with PFKFB3 serving as a case study. For this investigation, bioactive compounds for PFKFB3 were identified from a compound library of 1364 compounds via high-throughput screening, with bioactive compounds being further characterized as either competitive or non-competitive for F6P. Using the F6P-competitive compounds, several structure based docking programs were assessed individually and in conjunction with a pharmacophore screening. The results showed that the tiered virtual screening approach, using pharmacophore screening in addition to structure-based docking, improved enrichments rates in 80% of cases, reduced CPU costs up to 7-fold, and lessened variability among different structure-based docking methods. The second study investigates the structural and kinetic characteristics of citrate inhibition on the heart PFKFB isoenzyme, PFKFB2. High levels of citrate, an intermediate of the TCA cycle, signify an abundance of biosynthetic precursors and that additional glucose need not be degraded for this purpose. Previous studies have noted that citrate acts as an important negative feed-back mechanism to limit glycolytic activity by inhibiting PFKFB enzymes, yet the structural and mechanistic details of citrate’s inhibition had not been determined. To study the molecular basis for citrate inhibition, the three-dimensional structures of the human and bovine PFKFB2 orthologues were solved, each in complex with citrate. For both cases, citrate primarily occupied the binding site of Fructose-6-phosphate (F6P), competitively blocking F6P from binding. Additionally, a carboxy arm of citrate extended into the γ-phosphate binding site of ATP, sterically and electrostatically blocking the catalytic binding mode for ATP. In the human orthologue, which utilized AMPPNP as an ATP analogue, conformational changes were observed in the 2-kinase domain as well as the binding mode for AMPPNP. This study gives new insights as to how the citrate-mediate negative feedback loop influences glycolytic flux through PFKFB enzymes.
Subjects/Keywords: PFKFB3; Virtual Screening; PFKFB2; Cancer
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APA (6th Edition):
Crochet, R. B. (2015). Insights into the Development of Chemotherapeutics Targeting PFKFB Enzymes. (Doctoral Dissertation). Louisiana State University. Retrieved from etd-11162015-154823 ; https://digitalcommons.lsu.edu/gradschool_dissertations/311
Chicago Manual of Style (16th Edition):
Crochet, Robert Blake. “Insights into the Development of Chemotherapeutics Targeting PFKFB Enzymes.” 2015. Doctoral Dissertation, Louisiana State University. Accessed January 19, 2021.
etd-11162015-154823 ; https://digitalcommons.lsu.edu/gradschool_dissertations/311.
MLA Handbook (7th Edition):
Crochet, Robert Blake. “Insights into the Development of Chemotherapeutics Targeting PFKFB Enzymes.” 2015. Web. 19 Jan 2021.
Vancouver:
Crochet RB. Insights into the Development of Chemotherapeutics Targeting PFKFB Enzymes. [Internet] [Doctoral dissertation]. Louisiana State University; 2015. [cited 2021 Jan 19].
Available from: etd-11162015-154823 ; https://digitalcommons.lsu.edu/gradschool_dissertations/311.
Council of Science Editors:
Crochet RB. Insights into the Development of Chemotherapeutics Targeting PFKFB Enzymes. [Doctoral Dissertation]. Louisiana State University; 2015. Available from: etd-11162015-154823 ; https://digitalcommons.lsu.edu/gradschool_dissertations/311
University of Rochester
3.
Park, Min Sun.
Computational Studies of Proteins: Dynamics and
Interactions with Small Molecules.
Degree: PhD, 2011, University of Rochester
URL: http://hdl.handle.net/1802/15859
► Understanding protein dynamics is important for drug design. G proteins play an important role in cellular signal transduction and are involved in many processes. They…
(more)
▼ Understanding protein dynamics is important for
drug design. G proteins play an important role in cellular signal
transduction and are involved in many processes. They are
heterotrimers consisting of , and subunits, and are maintained
in an inactive state by association in a bound complex. In the
standard model for signaling, the exchange of GDP for GTP on the G
subunit leads a conformational change and a dissociation of the G
subunit from the G subunits. The subunits are then free to
interact with diverse binding partners for downstream signal
transduction. To examine the role of protein flexibility in
molecular recognition by G TROSY-HSQC NMR studies with
site-specific 15N labeling of G tryptophan residue backbone and
indole amines were performed. The NMR experiments of free G protein
G heterodimer suggested that a particular tryptophan residue in
the binding interface is highly mobile. Molecular dynamics
simulations of the unbound G heterodimer were performed showing
that the GW99 is significantly more mobile than the other
tryptophans on the nanosecond timescale. Further, we performed
nanosecond-timescale molecular dynamics simulations to investigate
conformational changes and dynamics of G in the presence of
several binding partners: a high-affinity peptide (SIGK),
phosducin, and the GDP-bound subunit, and interpreted these in
conjunction with the NMR experiments.
Several studies have
suggested that disrupting interactions of the G protein subunits
with downstream binding partners might be a valuable strategy for
pharmaceutical development. We examined several docking and scoring
protocols for estimating binding affinities for a set of 830
ligands from the NCI diversity set to the G12 subunit and
compared these with IC50s measured in a competition ELISA with a
high-affinity peptidic ligand. The best-performing docking protocol
used a consensus score and ensemble docking and resulted in a
6-fold enrichment of high-affinity compounds in the top-ranked 5%
of the ligand data set.
To investigate the effects of multiple
protonation states on protein-ligand recognition, we generated
alternative protonation states for selected titratable groups of
ligands and receptors. The selection of states was based on the
predicted pK(a) of the unbound receptor and ligand and the
proximity of titratable groups of the receptor to the binding site.
Various ligand tautomer states were also considered. An independent
docking calculation was run for each state. The accuracies of these
approaches were compared, using a set of 176 protein-ligand
complexes (15 receptors) for which crystal structures and measured
binding affinities are available. The best agreement with
experiment was obtained when ligand poses from experimental crystal
structures were used. Generally, using an ensemble of all generated
protonation states of the ligand and receptor gave the best
correlation between calculated and measured
affinities.
Subjects/Keywords: Computational Chemistry; Virtual Screening; Protein-Protein Interaction
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APA ·
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APA (6th Edition):
Park, M. S. (2011). Computational Studies of Proteins: Dynamics and
Interactions with Small Molecules. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/15859
Chicago Manual of Style (16th Edition):
Park, Min Sun. “Computational Studies of Proteins: Dynamics and
Interactions with Small Molecules.” 2011. Doctoral Dissertation, University of Rochester. Accessed January 19, 2021.
http://hdl.handle.net/1802/15859.
MLA Handbook (7th Edition):
Park, Min Sun. “Computational Studies of Proteins: Dynamics and
Interactions with Small Molecules.” 2011. Web. 19 Jan 2021.
Vancouver:
Park MS. Computational Studies of Proteins: Dynamics and
Interactions with Small Molecules. [Internet] [Doctoral dissertation]. University of Rochester; 2011. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1802/15859.
Council of Science Editors:
Park MS. Computational Studies of Proteins: Dynamics and
Interactions with Small Molecules. [Doctoral Dissertation]. University of Rochester; 2011. Available from: http://hdl.handle.net/1802/15859
Vanderbilt University
4.
Kaufmann, Kristian Wallace.
Computational prediction of protein small molecule interfaces using ROSETTA.
Degree: PhD, Chemistry, 2011, Vanderbilt University
URL: http://hdl.handle.net/1803/14473
► Protein small molecule docking has focused on the modeling of small molecule flexibility and scoring of small molecules binding to fixed protein structures due to…
(more)
▼ Protein small molecule docking has focused on the modeling of small molecule flexibility and scoring of small molecules binding to fixed protein structures due to the inherent complexity of incorporating protein degrees of freedom. Recent developments in modeling of protein folding have opened the possibility of including protein degrees of freedom in small molecule protein interface modeling. ROSETTA, a protein modeling suite, has performed at the forefront of protein modeling in recent years. Its combination of knowledge based discrete sampling and knowledge based energy functions have pushed protein modeling to sub-angstrom accuracy.
In the dissertation existing ROSETTA sampling protocols and energy functions are discussed along with previous applications of Rosetta to a variety of protein modeling tasks including de Novo protein folding, comparative modeling, protein docking, and ligand docking with rigid small molecules. Expansion of ROSETTALIGAND to allowing simultaneous sampling of protein binding site flexibility and small molecule flexibility using a parallel knowledge based approach to both sampling and scoring is detailed. In a benchmark of small molecule docking the new method recovered a native-like binding mode in 9 of 10 cases when docked back into the parent crystal structure, while in 7 of 11 cases the protocol recovered a native-like binding mode when docked to a structure of the same protein crystallized with a different small molecule. The value of specializing energy scoring functions to specific ligand families is examined in the context of PDZ. Specialized energy functions are shown to improve prediction of binding energies upon mutation within PDZ domains and to predict specificity of peptides binding to the domains. We dock ligands to comparative models built by Rosetta and models from the 8th Critical Assessment of Structure Prediction. We find that 60% of cases produce a native-like model among the top ranked models indicating that comparative models can be used in predictions. Finally, an advanced case study in modeling a small molecule protein interface is described using serotonin bound to the serotonin transporter.
Advisors/Committee Members: Dr. Randy D. Blakely (committee member), Dr. Michael P. Stone (committee member), Dr. Brian O. Bachmann (committee member), Dr. Jens Meiler (Committee Chair).
Subjects/Keywords: homology modeling; virtual screening; drug design
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APA (6th Edition):
Kaufmann, K. W. (2011). Computational prediction of protein small molecule interfaces using ROSETTA. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14473
Chicago Manual of Style (16th Edition):
Kaufmann, Kristian Wallace. “Computational prediction of protein small molecule interfaces using ROSETTA.” 2011. Doctoral Dissertation, Vanderbilt University. Accessed January 19, 2021.
http://hdl.handle.net/1803/14473.
MLA Handbook (7th Edition):
Kaufmann, Kristian Wallace. “Computational prediction of protein small molecule interfaces using ROSETTA.” 2011. Web. 19 Jan 2021.
Vancouver:
Kaufmann KW. Computational prediction of protein small molecule interfaces using ROSETTA. [Internet] [Doctoral dissertation]. Vanderbilt University; 2011. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1803/14473.
Council of Science Editors:
Kaufmann KW. Computational prediction of protein small molecule interfaces using ROSETTA. [Doctoral Dissertation]. Vanderbilt University; 2011. Available from: http://hdl.handle.net/1803/14473
Freie Universität Berlin
5.
Schaller, David Andreas.
Synergistische Target Kombinationen gegen Adipositas: Fokus auf MCHR1/H3R Modulation.
Degree: 2020, Freie Universität Berlin
URL: http://dx.doi.org/10.17169/refubium-27504
► The continuing epidemic of overweight and obesity faces a lack of appropriate pharmaceutical treatment options to support health care systems. Although studied for decades, currently…
(more)
▼ The continuing epidemic of overweight and obesity faces a lack of appropriate pharmaceutical treatment options to support health care systems. Although studied for decades, currently available drugs only show low efficacy but serious or at least unpleasant side effects. Multi-target drugs hold promise to overcome the limitations of traditional pharmaceutics by modulating several nodes of the disease-relevant biological network. In this thesis, the multi-target concept was applied to macromolecular targets involved in obesity.
In order to identify target pairs useful as starting points for multi-target drug design, we applied a systematic data mining approach employing publicly available bioactivity data of small molecules binding to targets involved in obesity. The target pair with the highest molecular similarity among known active ligands was found to comprise of histamine H3 receptor (H3R) and melanin-concentrating hormone receptor 1 (MCHR1). Both proteins are part of the G-protein coupled receptor (GPCR) family and were extensively studied as potential obesity targets. Although antagonizing either receptor was efficient in rodent models of obesity, drug candidates failed to proof efficacy in clinical studies. To test the potential of H3R and MCHR1 in multi-target drug development, a shape-based
virtual screening campaign was conducted resulting in the selection of three small molecules. A subsequent in vitro evaluation revealed nanomolar affinity for all three molecules at both receptors.
Lead optimization against multiple targets can dramatically benefit from integration of structural data. Since H3R and MCHR1 lack experimental structural data for structure-based drug design, two novel methods were developed that support drug design campaigns based on homology models. H3R is part of the aminergic family of GPCRs, which share a conserved charged interaction between ligand and protein. This crucial interaction was incorporated into a ligand-guided homology modeling campaign revealing valuable insights into side chain conformations critical for appropriate ligand placement in H3R. A subsequent
virtual screening campaign followed by in vitro validation revealed two novel ligands with nanomolar affinity at H3R. MCHR1 is less well characterized and was found to contain several highly flexible residues in the ligand binding pocket, which hindered the translation of the ligand-guided homology modeling strategy to MCHR1. To include the high flexibility of binding site residues, the protein environment of water molecules in molecular dynamics simulations was analyzed to derive 3D pharmacophores for
virtual screening. Generated 3D pharmacophores were highly successful in a retrospective
virtual screening campaign in discriminating active MCHR1 ligands from decoys. This method was translated into a Python package (PyRod), where the source code was released publicly.
The results and methods developed in this thesis provide valuable tools to support the development of more efficient and safe anti-obesity medications. We…
Advisors/Committee Members: male (gender), Wolber, Gerhard (firstReferee), Kirchmair, Johannes (furtherReferee).
Subjects/Keywords: Obesity; Virtual Screening; 3D Pharmacophore; ddc:615
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APA ·
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APA (6th Edition):
Schaller, D. A. (2020). Synergistische Target Kombinationen gegen Adipositas: Fokus auf MCHR1/H3R Modulation. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-27504
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Schaller, David Andreas. “Synergistische Target Kombinationen gegen Adipositas: Fokus auf MCHR1/H3R Modulation.” 2020. Thesis, Freie Universität Berlin. Accessed January 19, 2021.
http://dx.doi.org/10.17169/refubium-27504.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Schaller, David Andreas. “Synergistische Target Kombinationen gegen Adipositas: Fokus auf MCHR1/H3R Modulation.” 2020. Web. 19 Jan 2021.
Vancouver:
Schaller DA. Synergistische Target Kombinationen gegen Adipositas: Fokus auf MCHR1/H3R Modulation. [Internet] [Thesis]. Freie Universität Berlin; 2020. [cited 2021 Jan 19].
Available from: http://dx.doi.org/10.17169/refubium-27504.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Schaller DA. Synergistische Target Kombinationen gegen Adipositas: Fokus auf MCHR1/H3R Modulation. [Thesis]. Freie Universität Berlin; 2020. Available from: http://dx.doi.org/10.17169/refubium-27504
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of New South Wales
6.
Moorthy , Manju Latha Krishna.
Inhibition of telomerase: an in silico study.
Degree: Medical Sciences, 2015, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/58020
;
https://unsworks.unsw.edu.au/fapi/datastream/unsworks:45308/SOURCE02?view=true
► Telomeres are DNA-protein structures at the ends of linear chromosomes essential for the maintenance of genomic stability. Telomerase activity is non-existent in the majority of…
(more)
▼ Telomeres are DNA-protein structures at the ends of linear chromosomes essential for the maintenance of genomic stability. Telomerase activity is non-existent in the majority of normal cells but is activated in 80-85% of tumour cell lines in essentially all types of cancer. This enzyme functions in cancer cells by maintaining the integrity of the telomeric ends rendering the cells ‘immortal’. The recognition of telomerase as a possible target for the treatment of cancer 20 years ago has stimulated a tremendous amount of research in this area. However, the binding modes and detailed inhibitory mechanisms of most classes of telomerase inhibitors are currently unknown. At present, there are no pharmaceuticals on the market that target telomeres or telomerase, albeit some compounds are undergoing clinical trials. This study was conducted to use pharmacophore models to (i) predict the binding modes of existing telomerase inhibitors and (ii) to use the information obtained in discovering novel telomerase inhibitors. In the first results chapter, the following types of training sets were used in inhibitor binding site studies by generating quantitative and common feature pharmacophores: nucleoside inhibitors, non-nucleoside inhibitors and a group of bisindoles. Based on the datasets, pharmacophore models were built using the Discovery Studio 3.5 software. The pharmacophore models were first refined, and then validated. Once the models were finalised, they were compared against each other in various ways to find hints regarding binding sites. The bisindoles whose mechanism of action was unknown were compared against the non-nucleoside inhibitor pharmacophores. A hypothetical model of binding sites was derived based on the clues obtained through the pharmacophore models. In the second results chapter, the pharmacophore models were used in database searching with the aim to retrieve novel telomerase inhibitors. The hits were filtered and evaluated using different methods and the top compounds were then tested in vitro using telospot and direct assays. The hits selected from the first search using only one database were not active. The search was then refined and two databases were searched, and hits again filtered, evaluated and tested. In the third results chapter, G-quadruplex stabilisers, which inhibit the action of telomerase by binding to the G-quadruplex structure formed by telomeres, were also analysed and pharmacophore models generated. Quantitative, common feature, complex based and structure based pharmacophores were explored for this type of inhibitors, and the hits from database searches evaluated using docking methods.
Advisors/Committee Members: Griffith, Renate, Medical Sciences, Faculty of Medicine, UNSW.
Subjects/Keywords: cancer; pharmacophore; telomerase; telomere; docking; virtual screening
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APA (6th Edition):
Moorthy , M. L. K. (2015). Inhibition of telomerase: an in silico study. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/58020 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:45308/SOURCE02?view=true
Chicago Manual of Style (16th Edition):
Moorthy , Manju Latha Krishna. “Inhibition of telomerase: an in silico study.” 2015. Doctoral Dissertation, University of New South Wales. Accessed January 19, 2021.
http://handle.unsw.edu.au/1959.4/58020 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:45308/SOURCE02?view=true.
MLA Handbook (7th Edition):
Moorthy , Manju Latha Krishna. “Inhibition of telomerase: an in silico study.” 2015. Web. 19 Jan 2021.
Vancouver:
Moorthy MLK. Inhibition of telomerase: an in silico study. [Internet] [Doctoral dissertation]. University of New South Wales; 2015. [cited 2021 Jan 19].
Available from: http://handle.unsw.edu.au/1959.4/58020 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:45308/SOURCE02?view=true.
Council of Science Editors:
Moorthy MLK. Inhibition of telomerase: an in silico study. [Doctoral Dissertation]. University of New South Wales; 2015. Available from: http://handle.unsw.edu.au/1959.4/58020 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:45308/SOURCE02?view=true
7.
Almeida, Jonathan Resende de.
Estudos de modelagem molecular e relação estrutura-atividade da acetilcolinesterase e inibidores em Mal de Alzheimer.
Degree: Mestrado, Física Biológica, 2011, University of São Paulo
URL: http://www.teses.usp.br/teses/disponiveis/60/60136/tde-21032011-102116/
;
► O Mal de Alzheimer é a causa mais importante de demência em idosos. A progressão dos sintomas da doença está associada com modificações estruturais nas…
(more)
▼ O Mal de Alzheimer é a causa mais importante de demência em idosos. A progressão dos sintomas da doença está associada com modificações estruturais nas sinapses colinérgicas em determinadas regiões cerebrais e, consequentemente, à diminuição do potencial de neurotransmissão colinérgica. Desta forma, o aumento da capacidade de neurotransmissão colinérgica constitui o mecanismo fundamental dos fármacos utilizados para o tratamento do Mal de Alzheimer. Atualmente, o único tratamento clínico eficaz para o Mal de Alzheimer (MA) é a utilização de inibidores da acetilcolinesterase (AChE). Os anticolinesterásicos são os fármacos mais promissores desenvolvidos até hoje, pois é a única classe terapêutica que mostrou melhora nos sintomas cognitivos do MA. Para esse projeto, foram utilizadas diferentes técnicas de modelagem molecular como estratégia de planejamento racional de fármacos, tendo como base os inibidores de Acetilcolinesterase (AChE) descritos na literatura além dos que possuem estruturas depositadas no PDB, incluindo alguns que já vêm sendo utilizados no tratamento do Mal de Alzheimer. O objetivo foi planejar e testar novos potenciais inibidores desse alvo terapêutico, na tentativa de obter e futuramente otimizar novos protótipos como futuros candidatos a fármacos em Mal de Alzheimer. Os objetivos estendem-se a propostas de novos potenciais protótipos, selecionados de bases de dados de compostos comerciais contendo propriedades de fármacos. Os screenings virtuais foram tendenciados às estruturas dos inibidores já reportados da literatura bem como ao padrão farmacofórico comum a eles, a ser modelado.
Alzheimer\'s disease is the leading cause of dementia in the elderly. The progression of symptoms is associated with structural changes in cholinergic synapses in specific brain regions and consequentely to decrease the potential of cholinergic neurotransmission. Thus, the increased capacity of cholinergic neurotransmission is the fundamental mechanism of the drugs used to treat Alzheimer\'s disease. Currently, the only effective clinical treatment for Alzheimer\'s (MA) is the use of inhibitors of acetylcholinesterase (AChE). Cholinesterase inhibitors are the most promising drugs developed so far, it is the only therapeutic class that showed improvement in cognitive symptoms of MA. For this project, we used different techniques of molecular modeling as a strategy for rational design of drugs based on inhibitors of acetylcholinesterase (AChE) in the literature than those which have structures deposited in the PDB, including some that have already been used in the treatment Alzheimer\'s disease.The objective was to design and test new potential inhibitors of therapeutic target in attempts to obtain and optimize future new prototypes as future drug candidates in Alzheimer\'s disease. The goals extend to proposals from potential new prototypes, selected from databases of commercial compounds containing properties of drugs. The virtual screenings were trends to structures of the inhibitors already reported in the…
Advisors/Committee Members: Silva, Carlos Henrique Tomich de Paula da.
Subjects/Keywords: acetylcholinesterase inhibitors; Alzheimers disease; inibidores da acetilcolinesterase; Mal de Alzheimer; screening virtual.; virtual screening.
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APA ·
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APA (6th Edition):
Almeida, J. R. d. (2011). Estudos de modelagem molecular e relação estrutura-atividade da acetilcolinesterase e inibidores em Mal de Alzheimer. (Masters Thesis). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/60/60136/tde-21032011-102116/ ;
Chicago Manual of Style (16th Edition):
Almeida, Jonathan Resende de. “Estudos de modelagem molecular e relação estrutura-atividade da acetilcolinesterase e inibidores em Mal de Alzheimer.” 2011. Masters Thesis, University of São Paulo. Accessed January 19, 2021.
http://www.teses.usp.br/teses/disponiveis/60/60136/tde-21032011-102116/ ;.
MLA Handbook (7th Edition):
Almeida, Jonathan Resende de. “Estudos de modelagem molecular e relação estrutura-atividade da acetilcolinesterase e inibidores em Mal de Alzheimer.” 2011. Web. 19 Jan 2021.
Vancouver:
Almeida JRd. Estudos de modelagem molecular e relação estrutura-atividade da acetilcolinesterase e inibidores em Mal de Alzheimer. [Internet] [Masters thesis]. University of São Paulo; 2011. [cited 2021 Jan 19].
Available from: http://www.teses.usp.br/teses/disponiveis/60/60136/tde-21032011-102116/ ;.
Council of Science Editors:
Almeida JRd. Estudos de modelagem molecular e relação estrutura-atividade da acetilcolinesterase e inibidores em Mal de Alzheimer. [Masters Thesis]. University of São Paulo; 2011. Available from: http://www.teses.usp.br/teses/disponiveis/60/60136/tde-21032011-102116/ ;
University of California – San Francisco
8.
Ferreira, Rafaela.
Combining virtual and high-throughput screening in the discovery of new cruzain inhibitors.
Degree: Chemistry and Chemical Biology, 2010, University of California – San Francisco
URL: http://www.escholarship.org/uc/item/2509g569
► Cruzain's importance as a therapeutic target for Chagas Disease has been well established, and there is a continuous effort to find inhibitors for this cysteine…
(more)
▼ Cruzain's importance as a therapeutic target for Chagas Disease has been well established, and there is a continuous effort to find inhibitors for this cysteine protease. Here I describe the use of both virtual and high throughput screening, followed by medicinal chemistry optimization, to identify and diversify inhibitors of cruzain. In the first study, reported in Chapter 1, virtual screening of the ZINC lead-like database led to the identification of two novel scaffolds of non-covalent cruzain inhibitors. Medicinal chemistry optimization of the most potent hit (Ki = 64 µM) resulted in a SAR series that included nanomolar inhbitors. However, more detailed studies on the most potent compounds revealed that they were aggregators. This study demonstrates for the first time an SAR due to aggregation. It is therefore a warning on the danger of considering SAR as definitive evidence for a specific mechanism of inhibition. Chapters 2-4 describe a collaboration with the NIH Chemical Genomics Center. We prospectively docked their 197,861 compound library, while they experimentally tested it versus cruzain by HTS. By running this side to side comparison, we were able to determine the main sources of false positives in HTS, to optimize a series of covalent reversible inhibitors found by HTS, and to evaluate in detail the false positives and false negatives from docking. Furthermore, five classes of non-covalent inhibitors were found, three of which were predicted by top scores in the dock ranked library. This study therefore indicates the potential for using virtual screening results to prioritize HTS hits. The work described here led to the identification of seven new classes of non covalent and one class of potent covalent reversible cruzain inhibitors. In addition, two high resolution crystal structures of this enzyme in complex with the new inhibitors were solved. Finally, this work highlights important lessons on the danger of simply interpreting SAR data, the false positives than can arise from HTS and docking, and the false negatives derived from docking.
Subjects/Keywords: Chemistry, Pharmaceutical; cruzain; high-throughput screening; virtual screening
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APA (6th Edition):
Ferreira, R. (2010). Combining virtual and high-throughput screening in the discovery of new cruzain inhibitors. (Thesis). University of California – San Francisco. Retrieved from http://www.escholarship.org/uc/item/2509g569
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ferreira, Rafaela. “Combining virtual and high-throughput screening in the discovery of new cruzain inhibitors.” 2010. Thesis, University of California – San Francisco. Accessed January 19, 2021.
http://www.escholarship.org/uc/item/2509g569.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ferreira, Rafaela. “Combining virtual and high-throughput screening in the discovery of new cruzain inhibitors.” 2010. Web. 19 Jan 2021.
Vancouver:
Ferreira R. Combining virtual and high-throughput screening in the discovery of new cruzain inhibitors. [Internet] [Thesis]. University of California – San Francisco; 2010. [cited 2021 Jan 19].
Available from: http://www.escholarship.org/uc/item/2509g569.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ferreira R. Combining virtual and high-throughput screening in the discovery of new cruzain inhibitors. [Thesis]. University of California – San Francisco; 2010. Available from: http://www.escholarship.org/uc/item/2509g569
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Universitat Rovira i Virgili
9.
Gimeno Vives, Aleix.
Identification by virtual screening of protein tyrosine phosphatase 1B and matrix metalloproteinase 13 inhibitors for the treatment of obesity and obesity-associated disorders.
Degree: Departament de Bioquímica i Biotecnologia, 2019, Universitat Rovira i Virgili
URL: http://hdl.handle.net/10803/666486
► Obesity is one of the major public health problems in the 21st century. The great economic expansion of the last decades in developed countries has…
(more)
▼ Obesity is one of the major public health problems in the 21st century. The great economic expansion of the last decades in developed countries has contributed to the increased consumption of unhealthy foods and the excessive usage of energy-saving technologies. These have in turn led to the development of unhealthy lifestyles and the consequent increase of obesity prevalence. Thus, obesity has emerged as a natural response to an unnatural environment. With the continuous increase in obese population in each generation, the prevalence of obesity-associated disorders such as type II diabetes and osteoarthritis is also on the rise, and the prospect of developing a medical therapy specific for each patient earns increasing interest. In this regard, the targets protein tyrosine phosphatase 1B (PTP1B) and matrix metalloproteinase 13 (MMP-13) are involved in both obesity and, respectively, type II diabetes mellitus and osteoarthritis. The present doctoral thesis focuses on developing
virtual screening strategies to identify compounds that modulate the activity of these two targets which may have a positive influence on both obesity and its associated disorders.
Advisors/Committee Members: [email protected] (authoremail), true (authoremailshow), Pujadas Anguiano, Gerard, (director), García Vallvé, Santiago, (director).
Subjects/Keywords: cribatge virtual; PTP1B; MMP-13; cribado virtual; virtual screening; Ciències de la salut; 577; 615
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APA (6th Edition):
Gimeno Vives, A. (2019). Identification by virtual screening of protein tyrosine phosphatase 1B and matrix metalloproteinase 13 inhibitors for the treatment of obesity and obesity-associated disorders. (Thesis). Universitat Rovira i Virgili. Retrieved from http://hdl.handle.net/10803/666486
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Gimeno Vives, Aleix. “Identification by virtual screening of protein tyrosine phosphatase 1B and matrix metalloproteinase 13 inhibitors for the treatment of obesity and obesity-associated disorders.” 2019. Thesis, Universitat Rovira i Virgili. Accessed January 19, 2021.
http://hdl.handle.net/10803/666486.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Gimeno Vives, Aleix. “Identification by virtual screening of protein tyrosine phosphatase 1B and matrix metalloproteinase 13 inhibitors for the treatment of obesity and obesity-associated disorders.” 2019. Web. 19 Jan 2021.
Vancouver:
Gimeno Vives A. Identification by virtual screening of protein tyrosine phosphatase 1B and matrix metalloproteinase 13 inhibitors for the treatment of obesity and obesity-associated disorders. [Internet] [Thesis]. Universitat Rovira i Virgili; 2019. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/10803/666486.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Gimeno Vives A. Identification by virtual screening of protein tyrosine phosphatase 1B and matrix metalloproteinase 13 inhibitors for the treatment of obesity and obesity-associated disorders. [Thesis]. Universitat Rovira i Virgili; 2019. Available from: http://hdl.handle.net/10803/666486
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
10.
Helander, Jonathan Dean.
Synthetic Agonists of Abscisic Acid Receptors and Their Metabolomic Effects on Plants.
Degree: Plant Biology, 2017, University of California – Riverside
URL: http://www.escholarship.org/uc/item/39k859cd
► Land plants respond to multiple abiotic stresses, including drought, through the signaling cascade induced by the phytohormone abscisic acid (ABA). Endogenous production, or externally applied…
(more)
▼ Land plants respond to multiple abiotic stresses, including drought, through the signaling cascade induced by the phytohormone abscisic acid (ABA). Endogenous production, or externally applied ABA has a major function of eliciting guard cell closure, ultimately lowering transpiration and increasing drought tolerance in plants. Accordingly, the mechanisms of action in which ABA facilitates this response have been popular targets for agricultural research and applications. However, ABA has a multitude of responses aside from stomatal closure that are important for plant's survival to abiotic stress. In response to limited water availability, the phytohormone is known to maintain primary root growth while decreasing shoot growth, increase osmolyte accumulation, inhibit seed germination, and is involved in substantial crosstalk with other phytohormones. These responses are dependent on a core ABA signaling pathway comprised of three components: the ABA receptors known as the PYRABACTIN RESISTANT/PYRABACTIN RESISTANT-LIKE/REGULATORY COMPONENT OF ABA RECEPTORs (PYR/PYL/RCARs), the clade A protein phosphatase 2Cs (PP2Cs), and the sucrose nonfermenting related subfamily 2 (SnRK2s).The ABA receptors are the first interactors with ABA within the pathway, and cluster into three clades (I, II, III) based on sequence identity. Additionally, these clades can be further grouped based on oligomeric preference; clades I and II are preferentially monomeric, while clade III is preferentially dimeric. While some research has been done on non-redundant functions of the PYL proteins, many of the ABA responses remain uncharacterized with respect to the differential contributions of the different receptors. Additionally, most of the published ABA-receptor agonists are either direct ABA analogs displaying pan-agonist activity, or are primarily active only on the dimeric subgroup of the receptors. It would thus be potentially beneficial to develop agonists that show preferential activation of the monomeric receptors, allowing for temporal activation and subsequent analysis of their biological relevance.In order to identify compounds with novel selectivities, preferably on the monomeric receptors, I used high-throughput virtual screening to evaluate compounds unbiased to previous, active scaffolds. This resulted in a series of chemically similar hits which showed potent activity on the monomeric receptors, and translated to some in vivo responses. This potent, monomeric-specific scaffold was optimized using structure-aided design, improving the in vivo responses. Using this probe molecule I provide data that suggest that monomeric and dimeric ABA receptors may differentially control metabolomic and transcriptional responses, but are adequate in seed germination inhibition and primary root elongation.
Subjects/Keywords: Molecular biology; Amino acids; Glucosinolates; High throughput screening; HTS; Metabolomics; Virtual screening
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APA (6th Edition):
Helander, J. D. (2017). Synthetic Agonists of Abscisic Acid Receptors and Their Metabolomic Effects on Plants. (Thesis). University of California – Riverside. Retrieved from http://www.escholarship.org/uc/item/39k859cd
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Helander, Jonathan Dean. “Synthetic Agonists of Abscisic Acid Receptors and Their Metabolomic Effects on Plants.” 2017. Thesis, University of California – Riverside. Accessed January 19, 2021.
http://www.escholarship.org/uc/item/39k859cd.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Helander, Jonathan Dean. “Synthetic Agonists of Abscisic Acid Receptors and Their Metabolomic Effects on Plants.” 2017. Web. 19 Jan 2021.
Vancouver:
Helander JD. Synthetic Agonists of Abscisic Acid Receptors and Their Metabolomic Effects on Plants. [Internet] [Thesis]. University of California – Riverside; 2017. [cited 2021 Jan 19].
Available from: http://www.escholarship.org/uc/item/39k859cd.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Helander JD. Synthetic Agonists of Abscisic Acid Receptors and Their Metabolomic Effects on Plants. [Thesis]. University of California – Riverside; 2017. Available from: http://www.escholarship.org/uc/item/39k859cd
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
11.
Pham, Minh Quan.
Bio-pharmacological screening on liver-protective and anti-hepatocarcinoma activities of Vietnam natural products : Etude par ciblage pharmacologique des propriétés hépatoprotectrices ou anti-hépatocarcimone de substances naturelles du Vietnam.
Degree: Docteur es, Pharmacologie, 2016, Université Toulouse III – Paul Sabatier
URL: http://www.theses.fr/2016TOU30042
► Le carcinome hépatocellulaire (HCC) est le cancer du foie le plus répandu et représente la seconde cause de décès par cancer dans le monde. Un…
(more)
▼ Le carcinome hépatocellulaire (HCC) est le cancer du foie le plus répandu et représente la seconde cause de décès par cancer dans le monde. Un mauvais pronostic et l'absence de traitement efficace en font un problème majeur de santé publique dans les pays en voie de développement, notamment en Asie du Sud-Est, justifiant pleinement la recherche de molécules ou d'approches thérapeutiques nouvelles contre l'HCC. Ce travail porte sur la recherche de molécules isolées de plantes vietnamiennes actives contre l'HCC. La première approche a consisté en un criblage pharmacologique de 33 substances naturelles qui a conduit à l'identification de 7 ent-kaurane diterpénoïdes isolés de Croton kongensis Gagnep. présentant des propriétés antiprolifératives originales. La seconde approche, par criblage in silico d'une banque de 354 substances naturelles, a permis d'identifier la solasonine comme inhibiteur de l'interaction mortalin - p53 induisant l'apoptose dans la lignée cellulaire humaine HepG2.
Human hepatocellular carcinoma (HCC) is the most common type of liver cancer, the second most common cause of death from cancer worldwide. A very poor prognosis and a lack of effective treatments make liver cancer a major public health problem, notably in less developed regions, particularly in Eastern Asia. This fully justifies the search of new molecules and therapeutic strategies against HCC. The present work focused on finding bioactive compounds from Vietnamese plants against HCC. The first approach used classical screening of 33 natural compounds which resulted in the identification of 7 ent-kaurane diterpenoids isolated from Croton kongensis Gagnep. as potential agents. The second approach aimed at identifying molecules that could abrogate the interaction between Mortalin and p53 by in silico screening of a database of 354 natural compounds, which allowed the identification of Solasonine as a potent inhibitor of p53 - mortalin interactions.
Advisors/Committee Members: Gairin, Jean-Edouard (thesis director).
Subjects/Keywords: Hépatocarcinome; Substances naturelles; Criblage pharmacologique; Criblage virtuel; Hepatocarcinoma; Natural substances; Pharmacological screening; Virtual screening
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Pham, M. Q. (2016). Bio-pharmacological screening on liver-protective and anti-hepatocarcinoma activities of Vietnam natural products : Etude par ciblage pharmacologique des propriétés hépatoprotectrices ou anti-hépatocarcimone de substances naturelles du Vietnam. (Doctoral Dissertation). Université Toulouse III – Paul Sabatier. Retrieved from http://www.theses.fr/2016TOU30042
Chicago Manual of Style (16th Edition):
Pham, Minh Quan. “Bio-pharmacological screening on liver-protective and anti-hepatocarcinoma activities of Vietnam natural products : Etude par ciblage pharmacologique des propriétés hépatoprotectrices ou anti-hépatocarcimone de substances naturelles du Vietnam.” 2016. Doctoral Dissertation, Université Toulouse III – Paul Sabatier. Accessed January 19, 2021.
http://www.theses.fr/2016TOU30042.
MLA Handbook (7th Edition):
Pham, Minh Quan. “Bio-pharmacological screening on liver-protective and anti-hepatocarcinoma activities of Vietnam natural products : Etude par ciblage pharmacologique des propriétés hépatoprotectrices ou anti-hépatocarcimone de substances naturelles du Vietnam.” 2016. Web. 19 Jan 2021.
Vancouver:
Pham MQ. Bio-pharmacological screening on liver-protective and anti-hepatocarcinoma activities of Vietnam natural products : Etude par ciblage pharmacologique des propriétés hépatoprotectrices ou anti-hépatocarcimone de substances naturelles du Vietnam. [Internet] [Doctoral dissertation]. Université Toulouse III – Paul Sabatier; 2016. [cited 2021 Jan 19].
Available from: http://www.theses.fr/2016TOU30042.
Council of Science Editors:
Pham MQ. Bio-pharmacological screening on liver-protective and anti-hepatocarcinoma activities of Vietnam natural products : Etude par ciblage pharmacologique des propriétés hépatoprotectrices ou anti-hépatocarcimone de substances naturelles du Vietnam. [Doctoral Dissertation]. Université Toulouse III – Paul Sabatier; 2016. Available from: http://www.theses.fr/2016TOU30042
University of Minnesota
12.
Kurbanov, Elbek.
Synthetic, Biochemical, X-ray Crystallographic, Computational and High-Throughput Screening Approaches Toward Anthrax Toxin Lethal Factor Inhibition.
Degree: PhD, Medicinal Chemistry, 2015, University of Minnesota
URL: http://hdl.handle.net/11299/192665
► The lethal factor (LF) enzyme secreted by Bacillus anthracis is chiefly responsible for anthrax-related cytotoxicity. In this dissertation, I present the computational design, synthesis, biochemical…
(more)
▼ The lethal factor (LF) enzyme secreted by Bacillus anthracis is chiefly responsible for anthrax-related cytotoxicity. In this dissertation, I present the computational design, synthesis, biochemical testing, structural biology, and virtual and high-throughput screening approaches to identify binding requirements for LF inhibition. To this end, we designed ~50 novel compounds to probe design principles and structural requirements for LF. Specifically, in Chapters 2 and 3, computational, synthetic, biochemical and structural biology methods to explore the underinvestigated LF S2′ binding subsite are described. We discovered that LF domain 3 is very flexible and results in a relatively unconstrained S2′ binding site region. Additionally, we found that the S1′ subsite can undergo a novel conformational change resulting in a previously unreported tunnel region, which we term S1′*, that we expect can further be explored to design potent and selective LF inhibitors. Using this novel LF configuration, we virtually screened ~11 million drug-like compounds for activity against LF and have identified a novel compound that inhibits LF with an IC50 of 126 μM. In the course of this work, we found that reliable representation of zinc and other transition metal centers in macromolecules is nontrivial, due to the complexity of the coordination environment and charge distribution at the catalytic center. In Chapter 7, I will present work on applying and optimizing quantum mechanical methods developed by the Truhlar group to accurately calculate bond dissociation energies at low computational cost for various representative Zn2+ and Cd2+ model systems. By analyzing errors, we developed a prescription for an optimal system fragmentation strategy for our models. With this scheme, we find that the EE-3B-CE method is able to reproduce 53 conventionally calculated bond energies with an average absolute error of only 0.59 kcal/mol. Therefore, one could use the EE 3B CE approximation to obtain accurate results for large systems and/or identify better parameters for Zn centers for use in virtual screening. Finally, we present the results of a large-scale in vitro HTS campaign of ~250,000 small-molecules against LF. After extensive validation, involving secondary assays and hit synthesis we were able to prioritize a key lead for further prosecution.
Subjects/Keywords: anthrax; computational chemistry; high-throughput screening; lethal factor; structure-based inhibitor design; virtual screening
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APA ·
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APA (6th Edition):
Kurbanov, E. (2015). Synthetic, Biochemical, X-ray Crystallographic, Computational and High-Throughput Screening Approaches Toward Anthrax Toxin Lethal Factor Inhibition. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/192665
Chicago Manual of Style (16th Edition):
Kurbanov, Elbek. “Synthetic, Biochemical, X-ray Crystallographic, Computational and High-Throughput Screening Approaches Toward Anthrax Toxin Lethal Factor Inhibition.” 2015. Doctoral Dissertation, University of Minnesota. Accessed January 19, 2021.
http://hdl.handle.net/11299/192665.
MLA Handbook (7th Edition):
Kurbanov, Elbek. “Synthetic, Biochemical, X-ray Crystallographic, Computational and High-Throughput Screening Approaches Toward Anthrax Toxin Lethal Factor Inhibition.” 2015. Web. 19 Jan 2021.
Vancouver:
Kurbanov E. Synthetic, Biochemical, X-ray Crystallographic, Computational and High-Throughput Screening Approaches Toward Anthrax Toxin Lethal Factor Inhibition. [Internet] [Doctoral dissertation]. University of Minnesota; 2015. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/11299/192665.
Council of Science Editors:
Kurbanov E. Synthetic, Biochemical, X-ray Crystallographic, Computational and High-Throughput Screening Approaches Toward Anthrax Toxin Lethal Factor Inhibition. [Doctoral Dissertation]. University of Minnesota; 2015. Available from: http://hdl.handle.net/11299/192665
Iowa State University
13.
Selvaraj, Dhanraj.
Using Google Cardboard to perform a visual field screening test.
Degree: 2018, Iowa State University
URL: https://lib.dr.iastate.edu/etd/16461
► The visual field test is used to detect areas on the retina where there is a loss of vision. The equipment used to conduct the…
(more)
▼ The visual field test is used to detect areas on the retina where there is a loss of vision. The equipment used to conduct the test is bulky and can cost a significant amount to patients to take the test. Google Cardboard is an inexpensive headset which is paired with a mobile phone to run virtual reality applications. In this work, a visual field screening test is developed to enable people to do an eye exam with a low-cost and portable device such as a Google Cardboard and a smart phone. The Google Cardboard application helps reduce the cost of performing a visual field test by enabling a patient to do a self-administered visual field test before going into a clinic or hospital to do a more detailed eye exam. The patient can perform the test at home and with greater frequency, indications of advancing vision loss can be identified and treated earlier to prevent any irreversible damage to the eye caused by diseases.
There is an increase in demand for virtual reality products due to its affordability, portability, and accessibility. It is making a significant impact in many industries, including the healthcare industry. Virtual reality can assist with patient rehab, simulate surgeries to train doctors, treating PTSD [1]. In this project, a Google Cardboard application is developed to perform a visual field screening test. A set of lights arranged in a 7 x 7 grid is switched on and off randomly. The user presses the button on the Google Cardboard headset and data is recorded in the application as to which light the user sees or not. This data is plotted and is helpful in evaluating any defect in the visual field of the patient. This application of low-cost and portable VR headsets can significantly reduce time and cost for taking visual field tests because such a device is accessible even in remote areas of the world where bulky medical equipment is limited.
Subjects/Keywords: Google Cardboard; Perimetry; Screening; Virtual reality; Virtual Reality Headset; Visual field test; Engineering
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APA ·
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APA (6th Edition):
Selvaraj, D. (2018). Using Google Cardboard to perform a visual field screening test. (Thesis). Iowa State University. Retrieved from https://lib.dr.iastate.edu/etd/16461
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Selvaraj, Dhanraj. “Using Google Cardboard to perform a visual field screening test.” 2018. Thesis, Iowa State University. Accessed January 19, 2021.
https://lib.dr.iastate.edu/etd/16461.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Selvaraj, Dhanraj. “Using Google Cardboard to perform a visual field screening test.” 2018. Web. 19 Jan 2021.
Vancouver:
Selvaraj D. Using Google Cardboard to perform a visual field screening test. [Internet] [Thesis]. Iowa State University; 2018. [cited 2021 Jan 19].
Available from: https://lib.dr.iastate.edu/etd/16461.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Selvaraj D. Using Google Cardboard to perform a visual field screening test. [Thesis]. Iowa State University; 2018. Available from: https://lib.dr.iastate.edu/etd/16461
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of South Florida
14.
Metcalf, Rainer.
Constituent Partitioning Consensus Docking Models and Application in Drug Discovery.
Degree: 2019, University of South Florida
URL: https://scholarcommons.usf.edu/etd/8058
► This work expounds on some of the current computational tools and programs available and the best practices associated with their use. A high-level introduction, intended…
(more)
▼ This work expounds on some of the current computational tools and programs available and the best practices associated with their use. A high-level introduction, intended for both novices and the semi-experienced, focusing on the more common programs used in scientific literature is the scope of this topic. Both classical and quantum techniques are described. Classical methodologies include Molecular Dynamics, Monte Carlo, energy minimization methods, molecular docking, low-mode, and homology modeling. Quantum chemistry techniques are also discussed encompassing Hartree-Fock, Post-Hartree-Fock theories, and Density Functional Theory along with associated basis sets.
Along with established methodologies, novel theoretical methods are introduced for furthering the application of computational modeling. Constituent partitioning consensus docking makes use of disparate docking methodologies to elucidate physical characteristics of protein binding sites. This opus also advances the function of virtual target screening, implementing robust algorithmic treatment of the protocol and improving the accuracy and scope of target identification and binding site description. The introduction focuses on theoretical approaches while subsequent chapters encompass the execution of these techniques in practical applications of drug discovery.
Subjects/Keywords: Computational chemistry software; Virtual Molecular Modeling; Virtual Target Screening; Biochemistry; Other Education
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Metcalf, R. (2019). Constituent Partitioning Consensus Docking Models and Application in Drug Discovery. (Thesis). University of South Florida. Retrieved from https://scholarcommons.usf.edu/etd/8058
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Metcalf, Rainer. “Constituent Partitioning Consensus Docking Models and Application in Drug Discovery.” 2019. Thesis, University of South Florida. Accessed January 19, 2021.
https://scholarcommons.usf.edu/etd/8058.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Metcalf, Rainer. “Constituent Partitioning Consensus Docking Models and Application in Drug Discovery.” 2019. Web. 19 Jan 2021.
Vancouver:
Metcalf R. Constituent Partitioning Consensus Docking Models and Application in Drug Discovery. [Internet] [Thesis]. University of South Florida; 2019. [cited 2021 Jan 19].
Available from: https://scholarcommons.usf.edu/etd/8058.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Metcalf R. Constituent Partitioning Consensus Docking Models and Application in Drug Discovery. [Thesis]. University of South Florida; 2019. Available from: https://scholarcommons.usf.edu/etd/8058
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pretoria
15.
[No author].
Structure-based drug discovery against a novel
antimalarial drug target, S-adenosylmethionine
decarboxylase/ornithine decarboxylase
.
Degree: 2013, University of Pretoria
URL: http://upetd.up.ac.za/thesis/available/etd-02072013-141253/
► Malaria is one of the most life-threatening diseases affecting mankind, with over 3 billion people being at risk of infection, with most of these people…
(more)
▼ Malaria is one of the most life-threatening diseases
affecting mankind, with over 3 billion people being at risk of
infection, with most of these people living in Africa, South
America and Asia. As the malaria parasite is rapidly becoming
resistant to many of the possible treatments on the market, it is
of upmost importance to identify new possible drug targets and
describe drugs against these that are inexpensive, easy to
manufacture and have a long shelf-life in order to combat malaria.
One such target is the polyamine pathway. The polyamines
putrescine, spermidine, and spermine are crucial for cell
differentiation and proliferation. Interference with polyamine
biosynthesis by inhibition of the rate-limiting enzymes ornithine
decarboxylase (ODC) and S-adenosylmethionine decarboxylase
(AdoMetDC) has been discussed as a potential chemotherapy of cancer
and parasitic infections. Usually, both enzymes are individually
transcribed and highly regulated as monofunctional proteins.
However, ODC and AdoMetDC from P. falciparum (PfODC and PfAdoMetDC,
respectively) are found as a unique bifunctional protein
(PfAdoMetDC/ODC) in the malaria parasite, making it an enticing
target for new, selective antimalarial chemotherapies. In order to
apply structure-based drug discovery strategies to design
inhibitors for PfAdoMetDC/ODC, the atomic resolution structures of
these proteins are needed. Each individual domain has had its
structure proposed through homology modelling; however atomic
resolution structures of these domains are not yet available. The
homology model of PfAdoMetDC/ODC has not yet been elucidated due to
the interactions between the domains of the bifunctional protein
not being fully understood. High levels of recombinant expression
of the bifunctional protein have been either unsuccessful or
resulted in the formation of insoluble proteins being produced. The
purpose of this project is to optimise the recombinant expression
of PfAdoMetDC/ODC, and the PfODC domain, to produce high yields of
pure, soluble protein for subsequent atomic resolution structure
determination. Ultimately, this will enable the utilisation of
PfAdoMetDC/ODC in structure-based drug discovery strategies.
Overexpression of P. falciparum proteins in E. coli is notoriously
difficult, mainly due to the codon bias between the two species.
Comparative studies were performed on four constructs of the
PfAdoMetDC/ODC gene, containing either the wild-type, fully codon
harmonised, or partially codon harmonised gene sequences to analyse
the effect codon harmonisation had on protein expression and
activity of both domains of PfAdoMetDC/ODC as well as on the
monofunctional PfODC domain. Codon harmonisation did not improve
the expression levels or the purity of recombinantly expressed
PfAdoMetDC/ODC or the monofunctional PfODC domain. Truncated
versions of both proteins, and contamination by the E. coli
chaperone proteins DnaK and GroEL, were present in the protein
samples even after purification by affinity chromatography.
However, codon harmonisation improved…
Advisors/Committee Members: Prof L Birkholtz (advisor), Prof A I Louw (advisor).
Subjects/Keywords: Pfadometdc/odc;
Codon harmonisation;
Virtual screening;
Malaria;
UCTD
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APA (6th Edition):
author], [. (2013). Structure-based drug discovery against a novel
antimalarial drug target, S-adenosylmethionine
decarboxylase/ornithine decarboxylase
. (Masters Thesis). University of Pretoria. Retrieved from http://upetd.up.ac.za/thesis/available/etd-02072013-141253/
Chicago Manual of Style (16th Edition):
author], [No. “Structure-based drug discovery against a novel
antimalarial drug target, S-adenosylmethionine
decarboxylase/ornithine decarboxylase
.” 2013. Masters Thesis, University of Pretoria. Accessed January 19, 2021.
http://upetd.up.ac.za/thesis/available/etd-02072013-141253/.
MLA Handbook (7th Edition):
author], [No. “Structure-based drug discovery against a novel
antimalarial drug target, S-adenosylmethionine
decarboxylase/ornithine decarboxylase
.” 2013. Web. 19 Jan 2021.
Vancouver:
author] [. Structure-based drug discovery against a novel
antimalarial drug target, S-adenosylmethionine
decarboxylase/ornithine decarboxylase
. [Internet] [Masters thesis]. University of Pretoria; 2013. [cited 2021 Jan 19].
Available from: http://upetd.up.ac.za/thesis/available/etd-02072013-141253/.
Council of Science Editors:
author] [. Structure-based drug discovery against a novel
antimalarial drug target, S-adenosylmethionine
decarboxylase/ornithine decarboxylase
. [Masters Thesis]. University of Pretoria; 2013. Available from: http://upetd.up.ac.za/thesis/available/etd-02072013-141253/
University of California – San Diego
16.
Offutt, Tavina.
Studying Proteins Implicated in Cancer with a Computational Toolbox.
Degree: Chemistry, 2017, University of California – San Diego
URL: http://www.escholarship.org/uc/item/4rw973hd
► Cancer formation is a complex, multi-step process that allows cells to grow abnormally and potentially invade and spread throughout the body. A single genetic or…
(more)
▼ Cancer formation is a complex, multi-step process that allows cells to grow abnormally and potentially invade and spread throughout the body. A single genetic or structural alteration of a single protein in a cellular physiological process is enough to stimulate cancer formation. In treating cancer, a ‘targeted therapy’ approach is becoming increasingly common, where we can develop drugs that specifically target these altered proteins implicated in cancer. Two proteins that are heavily involved in several human cancers are protein kinases and p53, which are the focus of this dissertation work. I chose to use molecular dynamics simulations and in silico virtual screening, two methods from the computational chemistry toolbox in studying protein kinases and p53. I demonstrate that performing molecular dynamics is worthwhile in conducting virtual screens against protein kinases, because it may result in that at least one conformation is more predictive than the crystal structure. I also reveal key insight into the transcriptional activation mechanism of p53, and show how this mechanism is altered as a result of the R175H cancer mutation.
Subjects/Keywords: Computational chemistry; cancer; molecular dynamics; p53; protein kinases; virtual screening
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APA (6th Edition):
Offutt, T. (2017). Studying Proteins Implicated in Cancer with a Computational Toolbox. (Thesis). University of California – San Diego. Retrieved from http://www.escholarship.org/uc/item/4rw973hd
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Offutt, Tavina. “Studying Proteins Implicated in Cancer with a Computational Toolbox.” 2017. Thesis, University of California – San Diego. Accessed January 19, 2021.
http://www.escholarship.org/uc/item/4rw973hd.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Offutt, Tavina. “Studying Proteins Implicated in Cancer with a Computational Toolbox.” 2017. Web. 19 Jan 2021.
Vancouver:
Offutt T. Studying Proteins Implicated in Cancer with a Computational Toolbox. [Internet] [Thesis]. University of California – San Diego; 2017. [cited 2021 Jan 19].
Available from: http://www.escholarship.org/uc/item/4rw973hd.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Offutt T. Studying Proteins Implicated in Cancer with a Computational Toolbox. [Thesis]. University of California – San Diego; 2017. Available from: http://www.escholarship.org/uc/item/4rw973hd
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Alberta
17.
Hosamani, Ishwar V.
Homology modeling of Suv39h1 and discovery of its small
molecule inhibitors by virtual screening and their in vitro
validation.
Degree: MS, Department of Oncology, 2013, University of Alberta
URL: https://era.library.ualberta.ca/files/qj72p821p
► Epigenetic modifications are carried out by specific enzymes and are reversible making them a viable and attractive target to design inhibitors to reset the epigenetic…
(more)
▼ Epigenetic modifications are carried out by specific
enzymes and are reversible making them a viable and attractive
target to design inhibitors to reset the epigenetic regulatory
machinery of the cell and restore it to its normal state.
Suppressor of variegation 3-9 homolog 1 (Suv39h1) is a histone 3
lysine 9 (H3K9) trimethylase that plays an important role in
heterochromatin formation, mitosis, and its misregulation has been
implicated in several types of cancer. In this thesis, a homology
model of human Suv39h1 was constructed, optimized and validated and
used for virtual screening against several small molecule databases
to find its potential small molecule inhibitors. The binding sites
of three ligands i.e. S-Adenosyl Methionine, Chaetocin and
N-terminal of H3K9 peptide, on the homology model of Suv39h1 were
determined and used for virtual screening. The small molecules
predicted to bind to Suv39h1 with high affinity were tested by an
in vitro assay.
Subjects/Keywords: virtual screening; Homology modeling; histones; SUV39h1; methyltransferases; epigenetics
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Hosamani, I. V. (2013). Homology modeling of Suv39h1 and discovery of its small
molecule inhibitors by virtual screening and their in vitro
validation. (Masters Thesis). University of Alberta. Retrieved from https://era.library.ualberta.ca/files/qj72p821p
Chicago Manual of Style (16th Edition):
Hosamani, Ishwar V. “Homology modeling of Suv39h1 and discovery of its small
molecule inhibitors by virtual screening and their in vitro
validation.” 2013. Masters Thesis, University of Alberta. Accessed January 19, 2021.
https://era.library.ualberta.ca/files/qj72p821p.
MLA Handbook (7th Edition):
Hosamani, Ishwar V. “Homology modeling of Suv39h1 and discovery of its small
molecule inhibitors by virtual screening and their in vitro
validation.” 2013. Web. 19 Jan 2021.
Vancouver:
Hosamani IV. Homology modeling of Suv39h1 and discovery of its small
molecule inhibitors by virtual screening and their in vitro
validation. [Internet] [Masters thesis]. University of Alberta; 2013. [cited 2021 Jan 19].
Available from: https://era.library.ualberta.ca/files/qj72p821p.
Council of Science Editors:
Hosamani IV. Homology modeling of Suv39h1 and discovery of its small
molecule inhibitors by virtual screening and their in vitro
validation. [Masters Thesis]. University of Alberta; 2013. Available from: https://era.library.ualberta.ca/files/qj72p821p
University of Michigan
18.
Chan, Wallace.
Development and Application of Virtual Screening Methods for G Protein-Coupled Receptors.
Degree: PhD, Biological Chemistry, 2018, University of Michigan
URL: http://hdl.handle.net/2027.42/147623
► G protein-coupled receptors (GPCR) constitute one of the largest family of transmembrane proteins that have been implicated in a multitude of diseases, including cancer and…
(more)
▼ G protein-coupled receptors (GPCR) constitute one of the largest family of transmembrane proteins that have been implicated in a multitude of diseases, including cancer and diabetes, and have been an important target in drug deve lopment. While experiment-based high-throughput
screening for the unearthing of novel chemical compounds remains the de facto standard for drug discovery,
virtual screening has been gaining acceptance as an important complementary method due to its high speed and low cost, which instead employs computers.
This dissertation is aimed at the development of
virtual screening algorithms as applied to GPCR’s, in addition to the construction of GPCR-related databases (GPCR-EXP, GLASS). MAGELLAN is a ligand-based
virtual screening algorithm that makes inferences about what a GPCR would potentially bind based on sequence- and structure-based alignments. Building on top of this work, a sequential
virtual screening pipeline combining MAGELLAN with AutoDock Vina was constructed for the discovery of novel, bifunctional opioids with mu opioid receptor (MOR) agonist and delta opioid receptor (DOR) antagonist activity.
In the process of developing the
virtual screening algorithms, two GPCR-related databases were constructed to provide necessary data for the study. GPCR-EXP is a database of experimentally-validated and predicted GPCR structures. Important features include semi-manual curation of data, weekly updates, a user-friendly web interface, and high-resolution structure models with GPCR-I-TASSER, which many of the other GPCR-related databases lack. Additionally, GLASS database was developed in response to the absence of databases dedicated to GPCR experimental data. As a result, pharmacological data was pooled and integrated into a single source, resulting in over 500,000 unique GPCR-ligand associations; this made it the most comprehensive database of its kind thus far, providing the community with an accessible web interface, freely-available data, and ligands ready for docking.
MAGELLAN utilized pharmacological data from GLASS to infer from the ligands of sequence- and structure-based homologues what a target GPCR would bind. It was tested on two public
virtual screening databases (DUD-E and GPCR-Bench) and achieved an average EF of 9.75 and 13.70, respectively, which compared favorably with AutoDock Vina (1.48/3.16), DOCK 6 (2.12/3.47), and PoLi (2.2). Lastly, case studies with the mu opioid and motilin receptors demonstrated its applicability to
virtual screening in general, as well as GPCR de-orphanization. Subsequently, MAGELLAN was combined with AutoDock Vina into a novel, sequential
virtual screen pipeline against both MOR and DOR to compensate for the weaknesses of each algorithm. Retrospective
virtual screens against both MAGELLAN and AutoDock Vina were established for both receptors, and both methods were reported to have over-random discrimination between actives and decoys using the GPCR-Bench dataset.
In conclusion, structure (GPCR-EXP) and pharmacological data (GLASS)…
Advisors/Committee Members: Zhang, Yang (committee member), Traynor, John R (committee member), Andrews, Philip C (committee member), Carlson, Heather A (committee member), Saper, Mark A (committee member).
Subjects/Keywords: virtual screening; GPCR; Biological Chemistry; Pharmacy and Pharmacology; Health Sciences
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CSE |
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APA (6th Edition):
Chan, W. (2018). Development and Application of Virtual Screening Methods for G Protein-Coupled Receptors. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/147623
Chicago Manual of Style (16th Edition):
Chan, Wallace. “Development and Application of Virtual Screening Methods for G Protein-Coupled Receptors.” 2018. Doctoral Dissertation, University of Michigan. Accessed January 19, 2021.
http://hdl.handle.net/2027.42/147623.
MLA Handbook (7th Edition):
Chan, Wallace. “Development and Application of Virtual Screening Methods for G Protein-Coupled Receptors.” 2018. Web. 19 Jan 2021.
Vancouver:
Chan W. Development and Application of Virtual Screening Methods for G Protein-Coupled Receptors. [Internet] [Doctoral dissertation]. University of Michigan; 2018. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/2027.42/147623.
Council of Science Editors:
Chan W. Development and Application of Virtual Screening Methods for G Protein-Coupled Receptors. [Doctoral Dissertation]. University of Michigan; 2018. Available from: http://hdl.handle.net/2027.42/147623
University of Wollongong
19.
Rashad Ahmed, Adel Ahmed.
The medicinal chemistry development for new antimicrobial chemotherapeutics.
Degree: PhD, 2014, University of Wollongong
URL: 030401
Biologically
Active
Molecules,
030402
Biomolecular
Modelling
and
Design,
030403
Characterisation
of
Biological
Macromolecules
;
https://ro.uow.edu.au/theses/4132
► Chapter 2 discusses the synthesis of the arenearylpyrimidylmethanes (AAPMs) series was investigated to further develop the structure activity relationships (SAR) of these compounds as…
(more)
▼ Chapter 2 discusses the synthesis of the arenearylpyrimidylmethanes (AAPMs) series was investigated to further develop the structure activity relationships (SAR) of these compounds as potential anti-chikungunya virus agents. 1-(4,6-Dichloropyrimidin-5-yl)- 2-methyl-1-(3-nitrophenyl)propan-1-ol was prepared in 50% yield. Subsequent dehydration and amination gave the intermediate 4-amino-6-chloro-5-(2-methyl-1-(3- nitrophenyl)prop-1-en-1-yl)pyrimidine in 90% yield, over two steps. Final amination using either 1-amino-3-(diethylamino)propan-2-ol or N1,N1-diethylpentane-1,4-diamine was attempted using several conditions, however, the desired final AAPM derivatives were not obtained.
Further modification of the synthetic protocol was achieved through the replacement of the 4,6-dichloropyrimidine with the less hindered 4-chloropyridine. The 4- chloropyridin-3-yl alcohols were prepared in 42-52% yield. Subsequent dehydration afforded the 4-chloropyridine alkenes in 62-85% yield. Final replacement of the chlorine atom with the amine N1,N1-diethylpentane-1,4-diamine was attempted under different conditions, however, the desired products were not obtained. Instead the 3- (cyclobutylidene(4-phenoxypyridin-3-yl)methyl)aniline was isolated when using phenol as a solvent for the amination reaction. Replacement of the N1,N1-diethylpentane-1,4- diamine with the secondary amine morpholine gave 4-(3-(cyclopropylidene(3- nitrophenyl)methyl)pyridin-4-yl)morpholine in 65% yield.
Subjects/Keywords: Chikungunya virus; antiviral drug design; virtual screening; African sleeping sickness
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APA (6th Edition):
Rashad Ahmed, A. A. (2014). The medicinal chemistry development for new antimicrobial chemotherapeutics. (Doctoral Dissertation). University of Wollongong. Retrieved from 030401 Biologically Active Molecules, 030402 Biomolecular Modelling and Design, 030403 Characterisation of Biological Macromolecules ; https://ro.uow.edu.au/theses/4132
Chicago Manual of Style (16th Edition):
Rashad Ahmed, Adel Ahmed. “The medicinal chemistry development for new antimicrobial chemotherapeutics.” 2014. Doctoral Dissertation, University of Wollongong. Accessed January 19, 2021.
030401 Biologically Active Molecules, 030402 Biomolecular Modelling and Design, 030403 Characterisation of Biological Macromolecules ; https://ro.uow.edu.au/theses/4132.
MLA Handbook (7th Edition):
Rashad Ahmed, Adel Ahmed. “The medicinal chemistry development for new antimicrobial chemotherapeutics.” 2014. Web. 19 Jan 2021.
Vancouver:
Rashad Ahmed AA. The medicinal chemistry development for new antimicrobial chemotherapeutics. [Internet] [Doctoral dissertation]. University of Wollongong; 2014. [cited 2021 Jan 19].
Available from: 030401 Biologically Active Molecules, 030402 Biomolecular Modelling and Design, 030403 Characterisation of Biological Macromolecules ; https://ro.uow.edu.au/theses/4132.
Council of Science Editors:
Rashad Ahmed AA. The medicinal chemistry development for new antimicrobial chemotherapeutics. [Doctoral Dissertation]. University of Wollongong; 2014. Available from: 030401 Biologically Active Molecules, 030402 Biomolecular Modelling and Design, 030403 Characterisation of Biological Macromolecules ; https://ro.uow.edu.au/theses/4132
20.
Koensgen, Florian.
Modélisation du récepteur aux chimiokines C-C de type 5 : caractérisation des états conformationnels et conception rationnelle de modulateurs de la dimérisation : C-C chemokine receptor type 5 modelization : characterisation of conformational states and rational design of dimerization modulators.
Degree: Docteur es, Chimie informatique et théorique, 2018, Université de Strasbourg
URL: http://www.theses.fr/2018STRAF026
► De nombreuses études des RCPGs révèlent que leur activation n’implique pas que deux états conformationnels, l’un activé et l’autre inactivé, mais une diversité plus importante…
(more)
▼ De nombreuses études des RCPGs révèlent que leur activation n’implique pas que deux états conformationnels, l’un activé et l’autre inactivé, mais une diversité plus importante de ces états, impliquant également des états intermédiaires. Nous avons utilisé la simulation par dynamique moléculaire et l’analyse des interactions intramoléculaires non-covalentes pour étudier la plasticité structurale du récepteur CCR5 sous sa forme monomérique et dimérique. En couplant notre analyse avec diverses données expérimentales, nous avons pu proposer trois architectures dimériques du récepteur et associer des mouvements et des interactions clefs aux états conformationnels de CCR5 libre, lié à un agoniste, lié à un agoniste inverse et constitutivement activé ou inactivé par mutation d’acides aminés. Nous avons également développé une méthode d’identification des motifs d’interactions intramoléculaires transmembranaires, permettant de discriminer les états d’activations des RCPGs.
Many studies reveal that GPCR activation does not simply involve two conformational states, one activated and the other inactivated, but a variety of these states coupled to intermediate states. By using molecular dynamics simulations and analyzing non-covalent intramolecular interactions, we studied the structural plasticity of monomeric and dimeric CCR5. By coupling our analysis with various experimental data, we identified three dimeric organizations states of the receptor and associated key motions and intramolecular interactions to free CCR5, bound to an agonist, bound to an inverse agonist and constitutively activated or inactivated by mutated residues. We have also developed a method to identify intramolecular transmembrane interactions patterns, which allow the discrimination of GPCRs activation states.
Advisors/Committee Members: Rognan, Didier (thesis director), Kellenberger, Esther (thesis director).
Subjects/Keywords: Rcpg; CCR5; Criblage virtuel; Rcpg; CCR5; Virtual screening; Molecular dynamics; 541.2
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APA (6th Edition):
Koensgen, F. (2018). Modélisation du récepteur aux chimiokines C-C de type 5 : caractérisation des états conformationnels et conception rationnelle de modulateurs de la dimérisation : C-C chemokine receptor type 5 modelization : characterisation of conformational states and rational design of dimerization modulators. (Doctoral Dissertation). Université de Strasbourg. Retrieved from http://www.theses.fr/2018STRAF026
Chicago Manual of Style (16th Edition):
Koensgen, Florian. “Modélisation du récepteur aux chimiokines C-C de type 5 : caractérisation des états conformationnels et conception rationnelle de modulateurs de la dimérisation : C-C chemokine receptor type 5 modelization : characterisation of conformational states and rational design of dimerization modulators.” 2018. Doctoral Dissertation, Université de Strasbourg. Accessed January 19, 2021.
http://www.theses.fr/2018STRAF026.
MLA Handbook (7th Edition):
Koensgen, Florian. “Modélisation du récepteur aux chimiokines C-C de type 5 : caractérisation des états conformationnels et conception rationnelle de modulateurs de la dimérisation : C-C chemokine receptor type 5 modelization : characterisation of conformational states and rational design of dimerization modulators.” 2018. Web. 19 Jan 2021.
Vancouver:
Koensgen F. Modélisation du récepteur aux chimiokines C-C de type 5 : caractérisation des états conformationnels et conception rationnelle de modulateurs de la dimérisation : C-C chemokine receptor type 5 modelization : characterisation of conformational states and rational design of dimerization modulators. [Internet] [Doctoral dissertation]. Université de Strasbourg; 2018. [cited 2021 Jan 19].
Available from: http://www.theses.fr/2018STRAF026.
Council of Science Editors:
Koensgen F. Modélisation du récepteur aux chimiokines C-C de type 5 : caractérisation des états conformationnels et conception rationnelle de modulateurs de la dimérisation : C-C chemokine receptor type 5 modelization : characterisation of conformational states and rational design of dimerization modulators. [Doctoral Dissertation]. Université de Strasbourg; 2018. Available from: http://www.theses.fr/2018STRAF026
University of Cambridge
21.
Chee, Xavier.
Rational Development of New Inhibitors of Lipoteichoic Acid Synthase.
Degree: PhD, 2017, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/269766
► Staphyloccocus aureus is an opportunisitic pathogen that causes soft skin and tissue infections (SSTI) such as endocarditis, osteomyelitis and meningitis. In recent years, the re-emergence…
(more)
▼ Staphyloccocus aureus is an opportunisitic pathogen that causes soft skin and tissue infections (SSTI) such as endocarditis, osteomyelitis and meningitis. In recent years, the re-emergence of antibiotic-resistant S. aureus such as MRSA presents a formidable challenge for infection management worldwide. Amidst this global epidemic of antimicrobial resistance, several research efforts have turned their focus towards exploiting the cell-wall biosynthesis pathway for novel anti-bacterial targets. Recently, the lipoteichoic acid (LTA) biosynthesis pathway has emerged as a potential anti-bacterial target. LTA is an anionic polymer found on the cell envelope of Gram-positive bacteria. It comprises of repeating units of glycerol-phosphate (GroP) and is important for bacterial cell physiology and virulence. For example, it is critically involved in regulating ion homeostasis, cell division, host colonization and immune system invasion. Several reports showed that bacteria lacking LTA are unable to grow. At the same time, they suffer from severe cell division defects and also exhibit aberrant cell morphologies. The key protein involved in the LTA biosynthesis pathway is the Lipoteichoic acid synthase (LtaS). LtaS is located on the cell membrane of Gram-positive bacteria and can be divided into two parts: a transmembrane domain and an extra-cellular domain responsible for its enzymatic activity (annotated eLtaS). Given that LtaS is important for bacterial survival and there are no known eLtaS homologues in eukaryotic cells, this protein is an attractive antibacterial target. In 2013, a small molecule eLtaS inhibitor (termed 1771) was discovered. Although 1771 was able to deplete LTA production, the binding mechanism of 1771 to eLtaS remains unknown. Additionally, 1771 could only prolong the survival of infected mice temporarily because of its in vivo instability. Therefore, the need for finding more potent and metabolically stable inhibitors of eLtaS still remains.
Computational-aided drug design (CADD) is a cost-effective and useful approach that has been widely integrated into the drug discovery process. The protein eLtaS lends itself to be a good target for CADD since its crystal structure and a known inhibitor (with limited structure-activity data) is available. In this work, I have targeted eLtaS using CADD methodology followed by prospective validation using various biophysical, biochemical and microbiological assays.
My project can broadly be sub-divided into three phases: (a) identification of small molecule binding “hot spots”, (b) optimization of existing inhibitor and (c) discovery of new hits. Through a systematic use of different computational approaches, I
modelled a plausible 1771-bound eLtaS complex and used the structural insights to generate new inhibitors against eLtaS. To this end, I discovered EN-19, which is a more potent inhibitor of eLtaS. Additionally, by targeting transient cryptic pockets predicted by Molecular Dynamic simulations, I have discovered a new inhibitor chemotype that seems to exhibit a…
Subjects/Keywords: Virtual screening; Drug discovery; Antibiotics; Antimicrobial resistance; Computational drug design
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to Zotero / EndNote / Reference
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APA (6th Edition):
Chee, X. (2017). Rational Development of New Inhibitors of Lipoteichoic Acid Synthase. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/269766
Chicago Manual of Style (16th Edition):
Chee, Xavier. “Rational Development of New Inhibitors of Lipoteichoic Acid Synthase.” 2017. Doctoral Dissertation, University of Cambridge. Accessed January 19, 2021.
https://www.repository.cam.ac.uk/handle/1810/269766.
MLA Handbook (7th Edition):
Chee, Xavier. “Rational Development of New Inhibitors of Lipoteichoic Acid Synthase.” 2017. Web. 19 Jan 2021.
Vancouver:
Chee X. Rational Development of New Inhibitors of Lipoteichoic Acid Synthase. [Internet] [Doctoral dissertation]. University of Cambridge; 2017. [cited 2021 Jan 19].
Available from: https://www.repository.cam.ac.uk/handle/1810/269766.
Council of Science Editors:
Chee X. Rational Development of New Inhibitors of Lipoteichoic Acid Synthase. [Doctoral Dissertation]. University of Cambridge; 2017. Available from: https://www.repository.cam.ac.uk/handle/1810/269766
North-West University
22.
Barkhuizen, Melinda.
Screening of virtual libraries for monoamine oxidase inhibitors / Melinda Barkhuizen
.
Degree: 2013, North-West University
URL: http://hdl.handle.net/10394/10700
► The traditional view of drug design is that a single drug should interact with a single molecular target. As science progressed, there was an understanding…
(more)
▼ The traditional view of drug design is that a single drug should interact with a single
molecular target. As science progressed, there was an understanding that most drugs
interact with more than one target and that multiple targets may be responsible for either
adverse effects or additional therapeutic effects. The idea of polypharmacology, which
suggests that the focus of drug design should shift from a single drug that interacts with a
single target to a single drug that can have interactions with multiple targets and multiple
therapeutic effects, revolutionized the drug discovery process. Discovering new drugs is a
long and costly process with years of research and development and clinical trials required
before the drugs reach the market for much needed therapeutic applications. By repurposing
drugs that are already on the market for a new therapeutic target, the discovery process is
accelerated significantly.
One such a target disease, for which there is a great need for new effective therapies, is
Parkinson’s disease (PD). PD is a progressive neurodegenerative disease that is caused by
the death of dopaminergic neurons in the substantia nigra with the resulting loss of
dopamine from the striatum. Degeneration in PD leads to varying degrees of motor difficulty
and disability, along with other symptoms. Current therapies are focussed on symptomatic
management and an improvement of the quality of life of patients, rather than on a cure.
There are several therapeutic targets that are currently used in the treatment of PD. One of
those targets is the monoamine oxidase (MAO) enzymes, in particular the MAO-B isoform.
The MAO enzymes are responsible for the metabolism of amine neurotransmitters, such as
dopamine, and inhibition of MAO-B has proven to be an effective strategy to increase the
dopamine levels in the brain. Clinically, selective MAO-B inhibitors are administered
concurrently with levodopa (a precursor of dopamine) to increase the levels of dopamine
derived from levodopa. This approach prolongs the beneficial effects of levodopa.
Because MAO-A is responsible for the breakdown of noradrenalin, adrenalin, serotonin and
tyramine, non-selective and selective MAO-A inhibitors have therapeutic applications in
other neurological and psychiatric disorders such as depression. MAO-A inhibitors,
particularly irreversible inhibitors, are also notable from a toxicological point of view.
Irreversible MAO-A inhibitors may lead to potentially dangerous effects when combined with
serotonergic drugs and certain foods containing tyramine, such as cheeses and processed
meats. Selective MAO-B inhibitors and reversible MAO-A inhibitors appear to be free of
these interactions. Based on the considerations above, this study aimed to identify clinically used drugs which
also inhibit the MAO enzymes as a secondary pharmacological property. Such drugs may, in
theory, be repurposed as MAO inhibitors for therapeutic use in the treatment of PD and
depression. The identification of potential MAO-A…
Subjects/Keywords: Monoamine oxidase;
Repurposing;
Parkinson’s disease;
Virtual screening;
Toxicology;
Enzyme inhibition
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APA (6th Edition):
Barkhuizen, M. (2013). Screening of virtual libraries for monoamine oxidase inhibitors / Melinda Barkhuizen
. (Thesis). North-West University. Retrieved from http://hdl.handle.net/10394/10700
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Barkhuizen, Melinda. “Screening of virtual libraries for monoamine oxidase inhibitors / Melinda Barkhuizen
.” 2013. Thesis, North-West University. Accessed January 19, 2021.
http://hdl.handle.net/10394/10700.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Barkhuizen, Melinda. “Screening of virtual libraries for monoamine oxidase inhibitors / Melinda Barkhuizen
.” 2013. Web. 19 Jan 2021.
Vancouver:
Barkhuizen M. Screening of virtual libraries for monoamine oxidase inhibitors / Melinda Barkhuizen
. [Internet] [Thesis]. North-West University; 2013. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/10394/10700.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Barkhuizen M. Screening of virtual libraries for monoamine oxidase inhibitors / Melinda Barkhuizen
. [Thesis]. North-West University; 2013. Available from: http://hdl.handle.net/10394/10700
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Universitat Autònoma de Barcelona
23.
Tunca, Guzin.
A virtual screening procedure combining pharmacophore filtering and molecular docking with the LIE method.
Degree: Departament de Medicina, 2012, Universitat Autònoma de Barcelona
URL: http://hdl.handle.net/10803/284031
► Virtual screening plays a central role in the world of drug discovery today. In silico testing allows to screen millions of small molecules and to…
(more)
▼ Virtual screening plays a central role in the world of drug discovery today. In silico testing allows to screen millions of small molecules and to choose only the most promising ones for experimental testing. To find potential drug candidates, it is crucial to bring together individual and complementary computational tools. In this thesis, I describe an automated
virtual screening procedure that combines pharmacophore modeling and searches, high-throughput molecular docking, consensus scoring and binding free energy estimation with the linear interaction energy (LIE) method through molecular dynamics simulations.
One goal of this thesis was to build an evolving and versatile
virtual screening methodology, which enables integration of different tools at different steps. The procedure that started as a combination of a simple size filter, molecular docking and consensus scoring, advanced into an elaborate and automated computational workflow with the addition of pharmacophore searches and binding free energy estimation with LIE. This integrated method intends to compensate for weaknesses of individual structure-based techniques and allows the evaluation and comparison of the performance and accuracy of these techniques. Another important goal was to apply the computational workflow to target proteins and find hits that could be drug candidates. Experimental testing performed for human acid β-Glucosidase and bleomycin hydrolase indicate that several small molecules selected by the computational workflow display micromolar inhibitory activity. The standard LIE method used in this work was applied to more than ten thousand ligand-protein complexes for three different targets, which is, to our knowledge, the first time application of LIE at such large scale.
Advisors/Committee Members: [email protected] (authoremail), true (authoremailshow), Daura i Ribera, Xavier (director), true (authorsendemail).
Subjects/Keywords: Drug discovery; Virtual screening; Ligand binding; Ciències de la Salut; 577
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Tunca, G. (2012). A virtual screening procedure combining pharmacophore filtering and molecular docking with the LIE method. (Thesis). Universitat Autònoma de Barcelona. Retrieved from http://hdl.handle.net/10803/284031
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Tunca, Guzin. “A virtual screening procedure combining pharmacophore filtering and molecular docking with the LIE method.” 2012. Thesis, Universitat Autònoma de Barcelona. Accessed January 19, 2021.
http://hdl.handle.net/10803/284031.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Tunca, Guzin. “A virtual screening procedure combining pharmacophore filtering and molecular docking with the LIE method.” 2012. Web. 19 Jan 2021.
Vancouver:
Tunca G. A virtual screening procedure combining pharmacophore filtering and molecular docking with the LIE method. [Internet] [Thesis]. Universitat Autònoma de Barcelona; 2012. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/10803/284031.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Tunca G. A virtual screening procedure combining pharmacophore filtering and molecular docking with the LIE method. [Thesis]. Universitat Autònoma de Barcelona; 2012. Available from: http://hdl.handle.net/10803/284031
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Oxford
24.
Ebejer, Jean-Paul.
Data driven approaches to improve the drug discovery process : a virtual screening quest in drug discovery.
Degree: PhD, 2014, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:96d73300-f767-4ed6-8dda-a13a4aeb40e0
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596028
► Drug discovery has witnessed an increase in the application of in silico methods to complement existing in vitro and in vivo experiments, in an attempt…
(more)
▼ Drug discovery has witnessed an increase in the application of in silico methods to complement existing in vitro and in vivo experiments, in an attempt to 'fail fast' and reduce the high attrition rates of clinical phases. Computer algorithms have been successfully employed for many tasks including biological target selection, hit identification, lead optimization, binding affinity determination, ADME and toxicity prediction, side-effect prediction, drug repurposing, and, in general, to direct experimental work. This thesis describes a multifaceted approach to virtual screening, to computationally identify small-molecule inhibitors against a biological target of interest. Conformer generation is a critical step in all virtual screening methods that make use of atomic 3D data. We therefore analysed the ability of computational tools to reproduce high quality, experimentally resolved conformations of organic small-molecules. We selected the best performing method (RDKit), and developed a protocol that generates a non-redundant conformer ensemble which tends to contain low-energy structures close to those experimentally observed. We then outline the steps we took to build a multi-million, small-molecule database (including molecule standardization and efficient exact, substructure and similarity searching capabilities), for use in our virtual screening experiments. We generated conformers and descriptors for the molecules in the database. We tagged a subset of the database as `drug-like' and clustered this to provide a reduced, diverse set of molecules for use in more computationally-intensive virtual screening protocols. We next describe a novel virtual screening method we developed, called Ligity, that makes use of known protein-ligand holo structures as queries to search the small-molecule database for putative actives. Ligity has been validated against targets from the DUD-E dataset, and has shown, on average, better performance than other 3D methods. We also show that performance improved when we fused the results from multiple input structures. This bodes well for Ligity's future use, especially when considering that protein structure databases such as the Protein Data Bank are growing exponentially every year. Lastly, we describe the fruitful application of structure-based and ligand-based virtual screening methods to Plasmodium falciparum Subtilisin-like Protease 1 (PfSUB1), an important drug target in the human stages of the life-cycle of the malaria parasite. Our ligand-based virtual screening study resulted in the discovery of novel PfSUB1 inhibitors. Further lead optimization of these compounds, to improve binding affinity in the nanomolar range, may promote them as drug candidates. In this thesis we postulate that the accuracy of computational tools in drug discovery may be enhanced to take advantage of the exponential increase of experimental data and the availability of cheaper computational power such as cloud computing.
Subjects/Keywords: 615.1; Bioinformatics (life sciences); computational chemistry; virtual screening; drug discovery
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ebejer, J. (2014). Data driven approaches to improve the drug discovery process : a virtual screening quest in drug discovery. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:96d73300-f767-4ed6-8dda-a13a4aeb40e0 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596028
Chicago Manual of Style (16th Edition):
Ebejer, Jean-Paul. “Data driven approaches to improve the drug discovery process : a virtual screening quest in drug discovery.” 2014. Doctoral Dissertation, University of Oxford. Accessed January 19, 2021.
http://ora.ox.ac.uk/objects/uuid:96d73300-f767-4ed6-8dda-a13a4aeb40e0 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596028.
MLA Handbook (7th Edition):
Ebejer, Jean-Paul. “Data driven approaches to improve the drug discovery process : a virtual screening quest in drug discovery.” 2014. Web. 19 Jan 2021.
Vancouver:
Ebejer J. Data driven approaches to improve the drug discovery process : a virtual screening quest in drug discovery. [Internet] [Doctoral dissertation]. University of Oxford; 2014. [cited 2021 Jan 19].
Available from: http://ora.ox.ac.uk/objects/uuid:96d73300-f767-4ed6-8dda-a13a4aeb40e0 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596028.
Council of Science Editors:
Ebejer J. Data driven approaches to improve the drug discovery process : a virtual screening quest in drug discovery. [Doctoral Dissertation]. University of Oxford; 2014. Available from: http://ora.ox.ac.uk/objects/uuid:96d73300-f767-4ed6-8dda-a13a4aeb40e0 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596028
University of Edinburgh
25.
Yen, Li-Hsuan.
Inhibition of protein-peptide interactions by small molecules.
Degree: PhD, 2014, University of Edinburgh
URL: http://hdl.handle.net/1842/9978
► In all kinds of disease models, many proteins involved in protein-protein interactions (PPIs) are mutated and do not function properly. The important role of PPIs…
(more)
▼ In all kinds of disease models, many proteins involved in protein-protein interactions (PPIs) are mutated and do not function properly. The important role of PPIs in disease makes the design of small molecule inhibition an interesting proposition. This project looks at mouse double minute 2 (MDM2) and mouse double minute X (MDMX) which binds and inhibits the tumour suppressor protein p53. MDM2 and MDMX are therefore attractive therapeutic targets due to their role in tumour progression. The aim is to identify small molecule dual inhibitors that are able to disrupt MDM2 and MDMX from binding to p53. Both N-terminal MDM2 and MDMX were successfully expressed and purified with high purity and decent yield. These proteins were used to develop Fluoresence Polarization (FP) and Capillary Electrophoresis (CE) assays for small molecule inhibitors screening. This work has successfully developed FP and CE assays for detecting weakly interacting fragments. The CE assay is a novel method for detecting weak fragments for protein-protein interactions, which are a challenging target. Two approaches were employed to identify small molecule inhibitors for MDM2- N/p53 interaction. At first, small molecules were identified using in silico screening and these hits were verified using FP and CE assays. Second, analogue exploration was applied to identify fragments from the small molecule inhibitors discovered from the in silico screening. Diphenylamine and oxindole fragments were identified as the most potent. However, diphenylamine fragment was discovered to aggregate MDM2-N and was ranked as a false positive hit. No protein aggregation was found when incubated with the oxindole fragment. Therefore oxindole can provide a good starting point for the design of higher affinity analogues. Studying the interaction of MDMX has only recently been undertaken. MDMX contains a high homology binding site with MDM2. Hence, developing a dual MDM2/MDMX inhibitor has become an attractive target to focus on. FP and CE assays were developed to screen compounds against MDMX-N. In silico screening against MDM2-N and MDMX-N found several hits. One compound was discovered as a dual binder to MDM2-N and MDMX-N with low μM affinity. This novel hit is potentially a good starting point for the design of higher affinity analogues.
Subjects/Keywords: 572; MDM2; virtual screening; Fluoresence Polarization; CE assays; MDMX; fragments
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Yen, L. (2014). Inhibition of protein-peptide interactions by small molecules. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/9978
Chicago Manual of Style (16th Edition):
Yen, Li-Hsuan. “Inhibition of protein-peptide interactions by small molecules.” 2014. Doctoral Dissertation, University of Edinburgh. Accessed January 19, 2021.
http://hdl.handle.net/1842/9978.
MLA Handbook (7th Edition):
Yen, Li-Hsuan. “Inhibition of protein-peptide interactions by small molecules.” 2014. Web. 19 Jan 2021.
Vancouver:
Yen L. Inhibition of protein-peptide interactions by small molecules. [Internet] [Doctoral dissertation]. University of Edinburgh; 2014. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1842/9978.
Council of Science Editors:
Yen L. Inhibition of protein-peptide interactions by small molecules. [Doctoral Dissertation]. University of Edinburgh; 2014. Available from: http://hdl.handle.net/1842/9978
National University of Ireland – Galway
26.
Sessler, Tamas.
Regulators of TRAIL resistance in normal and transformed cells
.
Degree: 2015, National University of Ireland – Galway
URL: http://hdl.handle.net/10379/5061
► TRAIL is a member of the Tumor Necrosis Factor superfamily which was shown to be able to induce apoptotic cell death in a wide variety…
(more)
▼ TRAIL is a member of the Tumor Necrosis Factor superfamily which was shown to be able to induce apoptotic cell death in a wide variety of transformed cells, leaving normal, healthy cells unharmed. However, approximately 50-60% of the cancer cells were shown to be resistant to the cytotoxic effect of TRAIL, a large number of chemotherapeutics are being studied to broaden the efficacy of TRAIL. However the effect of these co-treatments on non-transformed cells is unpredictable as at present we do not have a proper understanding on the regulation behind the resistance of normal cells to TRAIL.
Preliminary works in our lab showed that in primary non-transformed cells TRAIL resistance is maintained by multiple anti-apoptotic proteins. In order to overcome the resistance toward TRAIL-induced apoptosis, the pathway has to be inhibited at two different stages by removal of anti-apoptotic proteins (cFLIP, Mcl-1, Bcl-2, Bcl-XL or XIAP). Using different transcription site searches we have identified the transcription factor Sp1 as a candidate for maintaining the expression levels of these anti-apoptotic proteins, which in turn is regulated by the activity of GSK3 and CDK1. In contrast to the observed redundancy in resistance mechanism to TRAIL seen in non-transformed cell lines, the majority of the cancer cell lines tend to rely on a single mechanism of resistance against TRAIL. This redundancy in TRAIL resistance in non-transformed cells indicate that there is a safe therapeutic window using TRAIL-based combination therapies, which targets a single, dominating resistance pathway. However knowledge of the mechanism of resistance should aid the choice of therapy.
TRAIL also activates non-apoptotic/inflammatory signaling, such as the NF-kappaB pathway which in certain cases may drive the resistance to TRAIL. In order to examine the involvement of this non-apoptotic pathway in TRAIL signaling, a reliable inhibitor would be needed that is able to uncouple the death ligand-mediated canonical NF-kappaB activation from apoptosis signaling. Using computer-aided drug design we have performed several
virtual screening methods to identify lead molecules that would be able to break up the interaction between TRADD and TRAF2 and thus selectively block death receptor induced NF-kappaB activation.
Advisors/Committee Members: Szegezdi, Eva (advisor).
Subjects/Keywords: TRAIL;
Apoptosis;
NF-kappaB;
Virtual screening;
Apoptosis Centre;
Biochemistry;
Natural Sciences
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Export
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Manager
APA (6th Edition):
Sessler, T. (2015). Regulators of TRAIL resistance in normal and transformed cells
. (Thesis). National University of Ireland – Galway. Retrieved from http://hdl.handle.net/10379/5061
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Sessler, Tamas. “Regulators of TRAIL resistance in normal and transformed cells
.” 2015. Thesis, National University of Ireland – Galway. Accessed January 19, 2021.
http://hdl.handle.net/10379/5061.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Sessler, Tamas. “Regulators of TRAIL resistance in normal and transformed cells
.” 2015. Web. 19 Jan 2021.
Vancouver:
Sessler T. Regulators of TRAIL resistance in normal and transformed cells
. [Internet] [Thesis]. National University of Ireland – Galway; 2015. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/10379/5061.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Sessler T. Regulators of TRAIL resistance in normal and transformed cells
. [Thesis]. National University of Ireland – Galway; 2015. Available from: http://hdl.handle.net/10379/5061
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Pretoria
27.
Reynolds, Jonathan
James.
Structure-based
drug discovery against a novel antimalarial drug target,
S-adenosylmethionine decarboxylase/ornithine
decarboxylase.
Degree: Biochemistry, 2012, University of Pretoria
URL: http://hdl.handle.net/2263/27172
► Malaria is one of the most life-threatening diseases affecting mankind, with over 3 billion people being at risk of infection, with most of these people…
(more)
▼ Malaria is one of the most life-threatening diseases
affecting mankind, with over 3 billion people being at risk of
infection, with most of these people living in Africa, South
America and Asia. As the malaria parasite is rapidly becoming
resistant to many of the possible treatments on the market, it is
of upmost importance to identify new possible drug targets and
describe drugs against these that are inexpensive, easy to
manufacture and have a long shelf-life in order to combat malaria.
One such target is the polyamine pathway. The polyamines
putrescine, spermidine, and spermine are crucial for cell
differentiation and proliferation. Interference with polyamine
biosynthesis by inhibition of the rate-limiting enzymes ornithine
decarboxylase (ODC) and S-adenosylmethionine decarboxylase
(AdoMetDC) has been discussed as a potential chemotherapy of cancer
and parasitic infections. Usually, both enzymes are individually
transcribed and highly regulated as monofunctional proteins.
However, ODC and AdoMetDC from P. falciparum (PfODC and PfAdoMetDC,
respectively) are found as a unique bifunctional protein
(PfAdoMetDC/ODC) in the malaria parasite, making it an enticing
target for new, selective antimalarial chemotherapies. In order to
apply structure-based drug discovery strategies to design
inhibitors for PfAdoMetDC/ODC, the atomic resolution structures of
these proteins are needed. Each individual domain has had its
structure proposed through homology modelling; however atomic
resolution structures of these domains are not yet available. The
homology model of PfAdoMetDC/ODC has not yet been elucidated due to
the interactions between the domains of the bifunctional protein
not being fully understood. High levels of recombinant expression
of the bifunctional protein have been either unsuccessful or
resulted in the formation of insoluble proteins being produced. The
purpose of this project is to optimise the recombinant expression
of PfAdoMetDC/ODC, and the PfODC domain, to produce high yields of
pure, soluble protein for subsequent atomic resolution structure
determination. Ultimately, this will enable the utilisation of
PfAdoMetDC/ODC in structure-based drug discovery strategies.
Overexpression of P. falciparum proteins in E. coli is notoriously
difficult, mainly due to the codon bias between the two species.
Comparative studies were performed on four constructs of the
PfAdoMetDC/ODC gene, containing either the wild-type, fully codon
harmonised, or partially codon harmonised gene sequences to analyse
the effect codon harmonisation had on protein expression and
activity of both domains of PfAdoMetDC/ODC as well as on the
monofunctional PfODC domain. Codon harmonisation did not improve
the expression levels or the purity of recombinantly expressed
PfAdoMetDC/ODC or the monofunctional PfODC domain. Truncated
versions of both proteins, and contamination by the E. coli
chaperone proteins DnaK and GroEL, were present in the protein
samples even after purification by affinity chromatography.
However, codon harmonisation improved…
Advisors/Committee Members: Birkholtz, Lyn-Marie (advisor), Louw, Abraham Izak (advisor).
Subjects/Keywords: Pfadometdc/odc; Codon
harmonisation; Virtual
screening;
Malaria;
UCTD
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APA ·
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Export
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Manager
APA (6th Edition):
Reynolds, J. (2012). Structure-based
drug discovery against a novel antimalarial drug target,
S-adenosylmethionine decarboxylase/ornithine
decarboxylase. (Masters Thesis). University of Pretoria. Retrieved from http://hdl.handle.net/2263/27172
Chicago Manual of Style (16th Edition):
Reynolds, Jonathan. “Structure-based
drug discovery against a novel antimalarial drug target,
S-adenosylmethionine decarboxylase/ornithine
decarboxylase.” 2012. Masters Thesis, University of Pretoria. Accessed January 19, 2021.
http://hdl.handle.net/2263/27172.
MLA Handbook (7th Edition):
Reynolds, Jonathan. “Structure-based
drug discovery against a novel antimalarial drug target,
S-adenosylmethionine decarboxylase/ornithine
decarboxylase.” 2012. Web. 19 Jan 2021.
Vancouver:
Reynolds J. Structure-based
drug discovery against a novel antimalarial drug target,
S-adenosylmethionine decarboxylase/ornithine
decarboxylase. [Internet] [Masters thesis]. University of Pretoria; 2012. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/2263/27172.
Council of Science Editors:
Reynolds J. Structure-based
drug discovery against a novel antimalarial drug target,
S-adenosylmethionine decarboxylase/ornithine
decarboxylase. [Masters Thesis]. University of Pretoria; 2012. Available from: http://hdl.handle.net/2263/27172
University of Tasmania
28.
Singh, V.
Applying bioinformatic tools to better understand eye diseases.
Degree: 2020, University of Tasmania
URL: Singh,
V
ORCID:
0000-0003-4847-3643
<https://orcid.org/0000-0003-4847-3643>
2020
,
'Applying
bioinformatic
tools
to
better
understand
eye
diseases',
PhD
thesis,
University
of
Tasmania.
► The highly specialized cells of the eye function in concert to produce clear vision, one of the most valued senses. Visual impairment or blindness can…
(more)
▼ The highly specialized cells of the eye function in concert to produce clear vision, one of the
most valued senses. Visual impairment or blindness can occur as a result of disease or trauma.
Age-related macular degeneration, glaucoma, cataracts and diabetic retinopathy are common
causes of vision loss in older individuals. This thesis explores the bioinformatics approaches
based on the central dogma as a model for exploring the experimental models for human eye
diseases including quality control of stem cells to detect chromosomal abnormalities;
epigenetic age prediction of ocular tissues; identification of novel genes in Clustered Regularly
Interspaced Short Palindromic Repeats (CRISPR) knockout screening in uveal melanoma; and
RNA-Seq analysis to understand the molecular mechanisms in oxygen-induced retinopathy
and differentiation of dental pulp mesenchymal stem cells into trabecular meshwork cells.
In a virtual karyotyping study, I investigated the utility of a low-density genome-wide SNP
array for the karyotypic assessment of human pluripotent stem cells (hPSCs) using the Illumina
Infinium HumanCore BeadChip. Specifically, the resolution of these arrays in detecting
chromosomal aberrations and their ability to identify clonal variations was determined. It was
shown that the SNP array can detect chromosomal abnormalities when at least 25% of the cell
population is aberrant. Our data demonstrate that an array-based karyotyping offers an
economical and robust sampling method, in the genomic resolution, compared with standard
cytogenetic karyotyping of hPSCs. This approach could provide a reliable, rapid and costeffective
assessment of hPSCs clonality and virtual karyotype for large-scale generation and
maintenance of hPSCs.
To investigate the effects of aging among different tissues, we calculated the DNA methylation
age of whole peripheral blood and ocular tissue from the same individual and compared it with
the person’s chronological age. We found significant differences between chronological and
epigenetic ages (p<0.048). Our study showed that there is a significant difference (mean = 44.4
years) between chronological and epigenetic age in neurosensory retinal tissue and the same
pattern identified by various tools.
Through a CRISPR knockout screening study, we used the Human GeCKOv2 pooled library
in OCM1 cell lines (uveal melanoma) to identify novel genes that are associated with
tumorigenesis using the CRISPRAnalyzeR tool on next-generation sequencing data. Overall,
from our analysis, we found 15 genes that have relatively low expression in the passage 12 as
compared to the passage 0 and are associated with the metabolic process, cellular process,
primary metabolic process, cellular metabolic process, biological process and organic
substance metabolic process. Our study shows that these genes are crucial for cell proliferation;
however, further in-vitro and in-vivo validation is required.
In RNA-Seq studies, we investigated the miRNA expression in oxygen-induced retinopathy
…
Subjects/Keywords: Bioinformatics; RNA-Seq; Virtual Karyotyping; CRISPR Screening; Epigenetic clock
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Manager
APA (6th Edition):
Singh, V. (2020). Applying bioinformatic tools to better understand eye diseases. (Thesis). University of Tasmania. Retrieved from Singh, V ORCID: 0000-0003-4847-3643 <https://orcid.org/0000-0003-4847-3643> 2020 , 'Applying bioinformatic tools to better understand eye diseases', PhD thesis, University of Tasmania.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Singh, V. “Applying bioinformatic tools to better understand eye diseases.” 2020. Thesis, University of Tasmania. Accessed January 19, 2021.
Singh, V ORCID: 0000-0003-4847-3643 <https://orcid.org/0000-0003-4847-3643> 2020 , 'Applying bioinformatic tools to better understand eye diseases', PhD thesis, University of Tasmania..
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Singh, V. “Applying bioinformatic tools to better understand eye diseases.” 2020. Web. 19 Jan 2021.
Vancouver:
Singh V. Applying bioinformatic tools to better understand eye diseases. [Internet] [Thesis]. University of Tasmania; 2020. [cited 2021 Jan 19].
Available from: Singh, V ORCID: 0000-0003-4847-3643 <https://orcid.org/0000-0003-4847-3643> 2020 , 'Applying bioinformatic tools to better understand eye diseases', PhD thesis, University of Tasmania..
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Singh V. Applying bioinformatic tools to better understand eye diseases. [Thesis]. University of Tasmania; 2020. Available from: Singh, V ORCID: 0000-0003-4847-3643 <https://orcid.org/0000-0003-4847-3643> 2020 , 'Applying bioinformatic tools to better understand eye diseases', PhD thesis, University of Tasmania.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Duquesne University
29.
Liu, Yi.
Structural Determinants for Inhibitor Recognition by the Dopamine Transporter.
Degree: PhD, Pharmacology-Toxicology, 2011, Duquesne University
URL: https://dsc.duq.edu/etd/829
► The dissertation will give an introduction, background and our research progress in the areas of dopamine transporter (DAT). A 3-D DAT computer model was generated…
(more)
▼ The dissertation will give an introduction, background and our research progress in the areas of dopamine transporter (DAT). A 3-D DAT computer model was generated in our laboratory based on the X-ray crystal structure of the bacterial leucine transporter LeuT, a distant homolog of DAT. The ability of this LeuTAa-based 3-D DAT computer model to identify specific DAT residues involved in inhibitor recognition was assessed through site-directed mutagenesis and subsequent pharmacologic characterization in the present study. Feedback from these experiments confirmed some of the suggestion from the DAT model, which is encouraging that the comparative DAT model is valid to some extent and could be further used for ligand docking and
virtual screening.
Advisors/Committee Members: Christopher K. Surratt, Jeffry Madura, Paula A. Witt-Enderby, David A. Johnson, Wilson S. Meng.
Subjects/Keywords: Dopamine transporter; Molecular model; Mutagenesis; Photoaffinity labeling; Virtual screening
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Chicago ·
MLA ·
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APA (6th Edition):
Liu, Y. (2011). Structural Determinants for Inhibitor Recognition by the Dopamine Transporter. (Doctoral Dissertation). Duquesne University. Retrieved from https://dsc.duq.edu/etd/829
Chicago Manual of Style (16th Edition):
Liu, Yi. “Structural Determinants for Inhibitor Recognition by the Dopamine Transporter.” 2011. Doctoral Dissertation, Duquesne University. Accessed January 19, 2021.
https://dsc.duq.edu/etd/829.
MLA Handbook (7th Edition):
Liu, Yi. “Structural Determinants for Inhibitor Recognition by the Dopamine Transporter.” 2011. Web. 19 Jan 2021.
Vancouver:
Liu Y. Structural Determinants for Inhibitor Recognition by the Dopamine Transporter. [Internet] [Doctoral dissertation]. Duquesne University; 2011. [cited 2021 Jan 19].
Available from: https://dsc.duq.edu/etd/829.
Council of Science Editors:
Liu Y. Structural Determinants for Inhibitor Recognition by the Dopamine Transporter. [Doctoral Dissertation]. Duquesne University; 2011. Available from: https://dsc.duq.edu/etd/829
University of Edinburgh
30.
Wang, Shao-Fang.
Biochemical and biophysical studies of MDM2-ligand interactions.
Degree: PhD, 2012, University of Edinburgh
URL: http://hdl.handle.net/1842/9527
► MDM2, murine double minute 2, is a RING type-E3 ligase protein and also an oncogene. MDM2 plays a critical role in determining the steady levels…
(more)
▼ MDM2, murine double minute 2, is a RING type-E3 ligase protein and also an oncogene. MDM2 plays a critical role in determining the steady levels and activity of p53 in cells using two mechanisms. The N-terminal domain of MDM2 binds to the transactivation domain of p53 and inhibits its transcriptional activity. The RING domain of MDM2 plays a role in the ubiquitination (and degradation) of p53. Several proteins are responsible for the ubiquitination mechanism including the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin ligase (E3). Since the E2-E3 interaction is essential for ubiquitination, the protein-protein recognition site is a potential drug target. Two different MDM2 RING constructs were expressed and purified: MDM2RING (residues 386-491) and MDM2RING△C (residues 386-478). Both constructs were characterised using dynamic light scattering, size exclusion chromatography, mass spectrometry, NMR and electron microscopy. E3 ligase activity in vitro was also studied. Taken together these results showed that the MDM2RING construct formed a concentration-dependent oligomeric structure. In contrast, the MDM2RING△C construct formed a dimer at all concentrations. Both MDM2RING and MDM2RING △ C retain E3 ligase activity. However, the MDM2RING△C construct is less active. Full length E2 enzyme UbcH5a was also purified. Various biophysical techniques were used to study its interaction with MDM2 as well as with potential small molecule inhibitors as in principle, small molecules which disrupt the interaction between MDM2 and UbcH5a, could prevent/promote ubiquitination of p53. The dimerisation of MDM2 is important for its E3 activity and the C8-binding site potentially provides a second druggable site. In this work, peptide 9, which has the same sequence as the C-terminus of MDMX (an MDM2 homologue) was found to inhibit MDM2 E3 activity. Various biological techniques including NMR, fluorescence anisotropy, and electrospray mass spectrometry were used to investigate the interaction between two inhibitory peptides and MDM2. A major part of project involved virtual screening (VS) to search for small molecules which can affect MDM2-dependent ubiquitination. Three potential targets were considered: (1) the C8-binding site of MDM2; (2) the UbcH5a-binding site of MDM2; and (3) the MDM2-binding site of UbcH5a. Several small molecules were identified using our virtual screening database-mining and docking programs that were shown to affect MDM2-dependent ubiquitination of p53. In terms of understanding the complex biochemical mechanism of MDM2 this work provides two interesting and functionally relevant observations: (i) the MDM2 RING△C construct is a dimer as this would not be expected form the existing studies, and has less E3 ligase activity than MDM2RING; (ii) small molecules that bind MDM2 on the E2 binding site enhanced E3 ligase activity. One model to explain these observations is that binding of small molecule activators family to the RING induces a change in the conformation of the Cterminal…
Subjects/Keywords: 572; MDM2; virtual screening; ligand; E3 ligase; ubiquitination
Record Details
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Record Details
Similar Records
Cite
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Wang, S. (2012). Biochemical and biophysical studies of MDM2-ligand interactions. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/9527
Chicago Manual of Style (16th Edition):
Wang, Shao-Fang. “Biochemical and biophysical studies of MDM2-ligand interactions.” 2012. Doctoral Dissertation, University of Edinburgh. Accessed January 19, 2021.
http://hdl.handle.net/1842/9527.
MLA Handbook (7th Edition):
Wang, Shao-Fang. “Biochemical and biophysical studies of MDM2-ligand interactions.” 2012. Web. 19 Jan 2021.
Vancouver:
Wang S. Biochemical and biophysical studies of MDM2-ligand interactions. [Internet] [Doctoral dissertation]. University of Edinburgh; 2012. [cited 2021 Jan 19].
Available from: http://hdl.handle.net/1842/9527.
Council of Science Editors:
Wang S. Biochemical and biophysical studies of MDM2-ligand interactions. [Doctoral Dissertation]. University of Edinburgh; 2012. Available from: http://hdl.handle.net/1842/9527
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Open Access Theses and Dissertations
