Cargando…
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...
Autores principales: | , |
---|---|
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 |
_version_ | 1783377241861783552 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6272817 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT awuniyaw reductionoffalsepositivesinstructurebasedvirtualscreeningwhenreceptorplasticityisconsidered AT muyuguang reductionoffalsepositivesinstructurebasedvirtualscreeningwhenreceptorplasticityisconsidered |