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In silico pharmacology in drug discovery: methods for binding affinity prediction, identifying protein-protein interaction breakers, and finding targets for small molecules

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Defense Thèse de doctorat : Univ. Genève, 2011 - Sc. 4295 - 2011/03/10
Abstract La présente thèse traite de la conception de médicaments assistée par ordinateur : 1) Prédiction d’affinité de liaison: La « steered molecular dynamics» a permis de distinguer des différences d’affinité d’analogues de substrats de la thymidine kinase 1 du virus de l’herpès simplex aussi faibles que 4.3 μM. 2) Prévention de l’agrégation d’un anticorps: La modélisation par homologie de l’agrégation primaire de bévacizumab, le « docking » et le « scaffold hopping » ont indiqué l’AMP comme prometteur pour prévenir l’agrégation. 3) Inhibiteurs d’une interaction protéine-protéine: 43 inhibiteurs potentiels de la NADPH oxidase 2 (NOX2) ont été identifiés par criblage virtuel. Le docking a suggéré un mode de liaison pour le célastrol, et une analyse d’interaction basée sur GRID a donné des peptides avec des affinités comparables au peptide natif. 4) Découverte de cibles: 80% des cibles de la phénazopyridine identifiées par criblage in silico inverse ont été confirmées.
Abstract The present thesis addresses different areas of Computer-Aided Drug Design: 1) Binding affinity prediction: Steered molecular dynamics allowed to distinguish affinity differences as small as 4.3 μM for substrate analogues of the Herpes Simplex Virus 1 Thymidine Kinase. 2) Aggregation breakers: Homology modelling of the primary aggregation of the monoclonal antibody bevacizumab as well as docking and scaffold hopping led to the identification of AMP as a promising antibody aggregation breaker. 3) Protein-protein interaction inhibitors: Virtual screening yielded 43 potential inhibitors of a protein-protein interface of the NADPH oxidase 2 (NOX2), docking led to a binding mode for celastrol, and a GRID-based interaction analysis identified peptides with binding affinities comparable to the native peptide. 4) Target discovery: Potential targets for phenazopyridine were identified by inverse in silico screening, of which 80% were confirmed experimentally.
Keywords Computer-aided drug designMolecular modellingBinding affinity predictionDockingMolecular dynamicsSteered molecular dynamicsVirtual screeningInverse virtual screeningThymidine kinaseMonoclonal antibodyCorticosteroidAggregation breakerNADPH oxidaseProtein-protein interaction inhibitorSmall moleculePeptideCelastrolTarget discoveryPhenazopyridineSelectivity
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URN: urn:nbn:ch:unige-1363338
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WESTERMAIER, Yvonne. In silico pharmacology in drug discovery: methods for binding affinity prediction, identifying protein-protein interaction breakers, and finding targets for small molecules. Université de Genève. Thèse, 2011. doi: 10.13097/archive-ouverte/unige:136333 https://archive-ouverte.unige.ch/unige:136333

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