Consensus Pharmacophore Strategy For Identifying Novel SARS-Cov-2 M Inhibitors from Large Chemical Libraries

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main Protease (M) is an enzyme that cleaves viral polyproteins translated from the viral genome and is critical for viral replication. M is a target for anti-SARS-CoV-2 drug development, and multiple M crystals complexed with competitive inhibitors have been reported. In this study, we aimed to develop an M 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 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 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 enzymatic activity finding that seven have inhibitory activity. Three compounds (1, 4, and 5) had IC values in the midmicromolar range. The M consensus pharmacophore reported herein can be used to identify compounds with improved activity and novel chemical scaffolds against M. 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.