Author, as appears in the article.: Macip, Guillem; Garcia-Segura, Pol; Mestres-Truyol, Julia; Saldivar-Espinoza, Bryan; Ojeda-Montes, Maria Jose; Gimeno, Aleix; Cereto-Massague, Adria; Garcia-Vallve, Santiago; Pujadas, Gerard;

Department: Bioquímica i Biotecnologia

URV's Author/s: Cereto Massagué, Adrián José / Garcia Vallve, Santiago / OJEDA MONTES, Mª JOSÉ / Pujadas Anguiano, Gerard / Saldivar Espinoza, Bryan Percy

Keywords: Virtual screening Site Sars-cov-2 3c protease Molecular docking Mechanism M-pro inhibitors Ligand Identification Glide Drug repurposing Discovery Covalent inhibitors Coronavirus Binding free-energy 3cl proteases

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(50) and docking scores is not good. Neither was any correlation found between the pIC(50) and the increment G calculated with an MM-GBSA method. When a group of experimentally known inactive compounds was added, neither the docking scores or the increment 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.

Thematic Areas: Pharmacology & pharmacy Pharmacology Molecular medicine Medicina i General medicine Drug discovery Ciências biológicas ii Ciências biológicas i Chemistry, medicinal

licence for use: https://creativecommons.org/licenses/by/3.0/es/

Author's mail: adrianjose.cereto@urv.cat gerard.pujadas@urv.cat santi.garcia-vallve@urv.cat adrianjose.cereto@urv.cat bryanpercy.saldivar@estudiants.urv.cat

Author identifier: 0000-0003-2598-8089 0000-0002-0348-7497 0000-0002-9667-2818

Record's date: 2023-04-01

Papper version: info:eu-repo/semantics/publishedVersion

Link to the original source: https://onlinelibrary.wiley.com/doi/10.1002/med.21862

Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/

Papper original source: Medicinal Research Reviews. 42 (2): 744-769

APA: Macip, Guillem; Garcia-Segura, Pol; Mestres-Truyol, Julia; Saldivar-Espinoza, Bryan; Ojeda-Montes, Maria Jose; Gimeno, Aleix; Cereto-Massague, Adria; (2022). Haste makes waste: A critical review of docking-based virtual screening in drug repurposing for SARS-CoV-2 main protease (M-pro) inhibition. Medicinal Research Reviews, 42(2), 744-769. DOI: 10.1002/med.21862

Article's DOI: 10.1002/med.21862

Entity: Universitat Rovira i Virgili

Journal publication year: 2022

Publication Type: Journal Publications