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Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered

Structure-based virtual screening for selecting potential drug candidates is usually challenged by how numerous false positives in a molecule library are excluded when receptor plasticity is considered. In this study, based on the binding energy landscape theory, a hypothesis that a true inhibitor c...

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Detalles Bibliográficos
Autores principales: Awuni, Yaw, Mu, Yuguang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272817/
https://www.ncbi.nlm.nih.gov/pubmed/25808156
http://dx.doi.org/10.3390/molecules20035152
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author Awuni, Yaw
Mu, Yuguang
author_facet Awuni, Yaw
Mu, Yuguang
author_sort Awuni, Yaw
collection PubMed
description Structure-based virtual screening for selecting potential drug candidates is usually challenged by how numerous false positives in a molecule library are excluded when receptor plasticity is considered. In this study, based on the binding energy landscape theory, a hypothesis that a true inhibitor can bind to different conformations of the binding site favorably was put forth, and related strategies to defeat this challenge were devised; reducing false positives when receptor plasticity is considered. The receptor in the study is the influenza A nucleoprotein, whose oligomerization is a requirement for RNA binding. The structural flexibility of influenza A nucleoprotein was explored by molecular dynamics simulations. The resultant distinctive structures and the crystal structure were used as receptor models in docking exercises in which two binding sites, the tail-loop binding pocket and the RNA binding site, were targeted with the Otava PrimScreen1 diversity-molecule library using the GOLD software. The intersection ligands that were listed in the top-ranked molecules from all receptor models were selected. Such selection strategy successfully distinguished high-affinity and low-affinity control molecules added to the molecule library. This work provides an applicable approach for reducing false positives and selecting true ligands from molecule libraries.
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spelling pubmed-62728172018-12-31 Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered Awuni, Yaw Mu, Yuguang Molecules Article Structure-based virtual screening for selecting potential drug candidates is usually challenged by how numerous false positives in a molecule library are excluded when receptor plasticity is considered. In this study, based on the binding energy landscape theory, a hypothesis that a true inhibitor can bind to different conformations of the binding site favorably was put forth, and related strategies to defeat this challenge were devised; reducing false positives when receptor plasticity is considered. The receptor in the study is the influenza A nucleoprotein, whose oligomerization is a requirement for RNA binding. The structural flexibility of influenza A nucleoprotein was explored by molecular dynamics simulations. The resultant distinctive structures and the crystal structure were used as receptor models in docking exercises in which two binding sites, the tail-loop binding pocket and the RNA binding site, were targeted with the Otava PrimScreen1 diversity-molecule library using the GOLD software. The intersection ligands that were listed in the top-ranked molecules from all receptor models were selected. Such selection strategy successfully distinguished high-affinity and low-affinity control molecules added to the molecule library. This work provides an applicable approach for reducing false positives and selecting true ligands from molecule libraries. MDPI 2015-03-19 /pmc/articles/PMC6272817/ /pubmed/25808156 http://dx.doi.org/10.3390/molecules20035152 Text en © 2015 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Awuni, Yaw
Mu, Yuguang
Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered
title Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered
title_full Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered
title_fullStr Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered
title_full_unstemmed Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered
title_short Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered
title_sort reduction of false positives in structure-based virtual screening when receptor plasticity is considered
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272817/
https://www.ncbi.nlm.nih.gov/pubmed/25808156
http://dx.doi.org/10.3390/molecules20035152
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