Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered
AbstractStructure-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
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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.
Awuni Y, Mu Y. Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered. Molecules. 2015; 20(3):5152-5164.Chicago/Turabian Style
Awuni, Yaw; Mu, Yuguang. 2015. "Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered." Molecules 20, no. 3: 5152-5164.