Cosolvent and Dynamic Effects in Binding Pocket Search by Docking Simulations.

P Bernát Szabó,Francesc Sabanés Zariquiey,Juan J Nogueira

doi:10.1021/acs.jcim.1c00924

Abstract

The lack of conformational sampling in virtual screening projects can lead to inefficient results because many of the potential drugs may not be able to bind to the target protein during the static docking simulations. Here, we performed ensemble docking for around 2000 United States Food and Drug Administration (FDA)-approved drugs with the RNA-dependent RNA polymerase (RdRp) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a target. The representative protein structures were generated by clustering classical molecular dynamics trajectories, which were evolved using three solvent scenarios, namely, pure water, benzene/water and phenol/water mixtures. The introduction of dynamic effects in the theoretical model showed improvement in docking results in terms of the number of strong binders and binding sites in the protein. Some of the discovered pockets were found only for the cosolvent simulations, where the nonpolar probes induced local conformational changes in the protein that lead to the opening of transient pockets. In addition, the selection of the ligands based on a combination of the binding free energy and binding free energy gap between the best two poses for each ligand provided more suitable binders than the selection of ligands based solely on one of the criteria. The application of cosolvent molecular dynamics to enhance the sampling of the configurational space is expected to improve the efficacy of virtual screening campaigns of future drug discovery projects.

Highlights

Proteins are ubiquitous building blocks playing a critical role in the reproduction, metabolism, and regulation of living organisms and viruses
Given the urgency of developing an effective treatment, most attempts to find new inhibitor substances were drug repurposing studies, targeting the virus’s RdRp14−18 or other important proteins.[19−22] The RNA-dependent RNA polymerase (RdRp) protein is an especially promising drug target as it is responsible for the replication of the viral RNA inside the host cell,[23] and it is highly similar to the RdRp of SARS-CoV,[24] which already has a number of verified inhibitors.[25]
First, the equilibration of the protein during the various molecular dynamics (MD) trajectories is examined by plotting the root-mean-square deviation (RMSD) of the protein structure from its initial state throughout the simulated time

Summary

Introduction

Proteins are ubiquitous building blocks playing a critical role in the reproduction, metabolism, and regulation of living organisms and viruses. The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to claim thousands of lives every day more than a year after its outbreak.[9] the knowledge and the developed tools to fight against it are vastly more potent than they were a year before.[10] Antiviral drugs targeting the proteins vital to the reproduction of SARS-CoV-2 have been the most important tools,[11] aside from vaccines that are being used as preventative measures. Its high-quality three-dimensional (3D) structure has been available from as early as April 2020.26 In large part, due to the urgent nature of the COVID-19 pandemic, most of the above-cited research projects relied heavily, or even exclusively, on computational techniques for the discovery of the potential inhibitors, due to the cost and time efficiency of such methods

Objectives

Results

Conclusion