Language
English
Publication Date
3-25-2024
Journal
Journal of Chemical Information and Modeling
DOI
10.1021/acs.jcim.3c01439
PMID
38472094
PMCID
PMC10966741
PubMedCentral® Posted Date
3-12-2024
PubMedCentral® Full Text Version
Post-print
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main Protease (Mpro) is an enzyme that cleaves viral polyproteins translated from the viral genome and is critical for viral replication. Mpro is a target for anti-SARS-CoV-2 drug development, and multiple Mpro crystals complexed with competitive inhibitors have been reported. In this study, we aimed to develop an Mpro consensus pharmacophore as a tool to expand the search for inhibitors. We generated a consensus model by aligning and summarizing pharmacophoric points from 152 bioactive conformers of SARS-CoV-2 Mpro inhibitors. Validation against a library of conformers from a subset of ligands showed that our model retrieved poses that reproduced the crystal-binding mode in 77% of the cases. Using models derived from a consensus pharmacophore, we screened >340 million compounds. Pharmacophore-matching and chemoinformatics analyses identified new potential Mpro inhibitors. The candidate compounds were chemically dissimilar to the reference set, and among them, demonstrating the relevance of our model. We evaluated the effect of 16 candidates on Mpro enzymatic activity finding that seven have inhibitory activity. Three compounds (1, 4, and 5) had IC50 values in the midmicromolar range. The Mpro consensus pharmacophore reported herein can be used to identify compounds with improved activity and novel chemical scaffolds against Mpro. The method developed for its generation is provided as an open-access code (https://github.com/AngelRuizMoreno/ConcensusPharmacophore) and can be applied to other pharmacological targets.
Keywords
Humans, SARS-CoV-2, COVID-19, Small Molecule Libraries, Pharmacophore, Consensus, Viral Nonstructural Proteins, Protease Inhibitors, Molecular Docking Simulation, Antiviral Agents
Published Open-Access
yes
Recommended Citation
Ruiz-Moreno, Angel J; Cedillo-González, Raziel; Cordova-Bahena, Luis; et al., "Consensus Pharmacophore Strategy For Identifying Novel SARS-Cov-2 Mpro Inhibitors from Large Chemical Libraries" (2024). The Brown Foundation: Institute of Molecular Medicine. 8.
https://digitalcommons.library.tmc.edu/molecular_med/8
Graphical Abstract