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Molecules 2015, 20(3), 5152-5164; doi:10.3390/molecules20035152

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

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
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Academic Editor: Rino Ragno
Received: 5 February 2015 / Revised: 9 March 2015 / Accepted: 16 March 2015 / Published: 19 March 2015
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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Abstract

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. View Full-Text
Keywords: virtual screening; receptor plasticity; false positives; docking; GOLD virtual screening; receptor plasticity; false positives; docking; GOLD
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Awuni, Y.; Mu, Y. Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered. Molecules 2015, 20, 5152-5164.

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