Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main Protease (M(pro)) is an enzyme that cleaves viral polyproteins translated from the viral genome and is critical for viral replication. M(pro) is a target for anti-SARS-CoV-2 drug development, and multiple M(pro) crystals complexed with competitive inhibitors have been reported. In this study, we aimed to develop an M(pro) 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(pro) 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(pro) 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(pro) enzymatic activity finding that seven have inhibitory activity. Three compounds (1, 4, and 5) had IC(50) values in the midmicromolar range. The M(pro) consensus pharmacophore reported herein can be used to identify compounds with improved activity and novel chemical scaffolds against M(pro). 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.