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

Molecules

Yaw Awuni²  Yuguang Mu¹ 

[1] School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore; E-Mail

关键词: virtual screening;    receptor plasticity;    false positives;    docking;    GOLD;   

DOI  :  10.3390/molecules20035152

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.