Haste Makes Waste: A Critical Review of Docking-based Virtual Screening in Drug Repurposing for SARS-CoV-2 Main Protease (M-pro) Inhibition

Overview

Journal Med Res Rev

Publisher Wiley

Specialties General Medicine
Pharmacology

Date 2021 Oct 26

PMID 34697818

Citations 33

Authors

Guillem Macip

Pol Garcia-Segura

Julia Mestres-Truyol

Bryan Saldivar-Espinoza

Maria Jose Ojeda-Montes

Aleix Gimeno

Adria Cereto-Massague

Santiago Garcia-Vallve

Gerard Pujadas

Affiliations

Soon will be listed here.

Abstract

This review makes a critical evaluation of 61 peer-reviewed manuscripts that use a docking step in a virtual screening (VS) protocol to predict SARS-CoV-2 M-pro (M-pro) inhibitors in approved or investigational drugs. Various manuscripts predict different compounds, even when they use a similar initial dataset and methodology, and most of them do not validate their methodology or results. In addition, a set of known 150 SARS-CoV-2 M-pro inhibitors extracted from the literature and a second set of 81 M-pro inhibitors and 113 inactive compounds obtained from the COVID Moonshot project were used to evaluate the reliability of using docking scores as feasible predictors of the potency of a SARS-CoV-2 M-pro inhibitor. Using two SARS-CoV-2 M-pro structures and five protein-ligand docking programs, we proved that the correlation between the pIC and docking scores is not good. Neither was any correlation found between the pIC and the ∆G calculated with an MM-GBSA method. When a group of experimentally known inactive compounds was added, neither the docking scores or the ∆G were able to distinguish between compounds with or without M-pro experimental inhibitory activity. Performances improved when covalent and noncovalent inhibitors were treated separately, but were not good enough to fully support using a docking score as a cutoff value for selecting new putative M-pro inhibitors or predicting the relative bioactivity of a compound by comparison with a reference compound. The two sets of known SARS-CoV-2 M-pro inhibitors presented here could be used for validating future VS protocols which aim to predict M-pro inhibitors.

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