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Consensus Pharmacophore Strategy For Identifying Novel SARS-Cov-2 M pro Inhibitors from Large Chemical Libraries.
- Source :
-
Journal of chemical information and modeling [J Chem Inf Model] 2024 Mar 25; Vol. 64 (6), pp. 1984-1995. Date of Electronic Publication: 2024 Mar 12. - Publication Year :
- 2024
-
Abstract
- The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main Protease (M <superscript>pro</superscript> ) is an enzyme that cleaves viral polyproteins translated from the viral genome and is critical for viral replication. M <superscript>pro</superscript> is a target for anti-SARS-CoV-2 drug development, and multiple M <superscript>pro</superscript> crystals complexed with competitive inhibitors have been reported. In this study, we aimed to develop an M <superscript>pro</superscript> 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 M <superscript>pro</superscript> 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 M <superscript>pro</superscript> 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 M <superscript>pro</superscript> enzymatic activity finding that seven have inhibitory activity. Three compounds (1, 4, and 5) had IC <subscript>50</subscript> values in the midmicromolar range. The M <superscript>pro</superscript> consensus pharmacophore reported herein can be used to identify compounds with improved activity and novel chemical scaffolds against M <superscript>pro</superscript> . 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.
Details
- Language :
- English
- ISSN :
- 1549-960X
- Volume :
- 64
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of chemical information and modeling
- Publication Type :
- Academic Journal
- Accession number :
- 38472094
- Full Text :
- https://doi.org/10.1021/acs.jcim.3c01439