Abstract 1553 Identification of a SARS-CoV-2 Mpro inhibitor from large chemical libraries using a consensus pharmacophore

SARS-CoV-2 Main Protease (Mpro) is an enzyme that cleavages viral polyproteins translated from the viral genome, being critical for viral replication. Thus, Mpro is a target for anti-SARS-CoV-2 drug development and multiple Mpro crystals complexed with competitive inhibitors have been reported. Here, we developed an open access code for generating a Mpro Consensus pharmacophore (https://github.com/AngelRuizMoreno/ConcensusPharmacophore). Our model was employed to search for potential inhibitors inhibitor among large chemical libraries. The activity of commercially available compounds was evaluated by fluorescence resonance energy transfer (FRET) assays. We generated a consensus model by aligning and summarizing pharmacophoric points from 152 bioactive conformers of SARS-CoV-2 Mpro inhibitors. The resulting model included 19 consensus descriptors for hydrogen acceptors, 20 for hydrogen donors, and 11 hydrophobic interactions. Validation against a library of conformers from a subset of ligands showed that our model retrieved poses that reproduce the crystal binding mode in 77% of the cases. Using models derived from the consensus pharmacophore, we screened >340 millions of compounds. Pharmacophore-matching and chemoinformatic analysis identified new potential Mpro inhibitors. The candidate compounds are chemically dissimilar to the reference set and among them, showing the relevance of our model. We evaluated the activity of one of the selected compounds, MolPort-035-411-009, on Mpro enzymatic activity, finding its IC50 in the mid micromolar range. The Mpro consensus pharmacophore reported here can be used to identify new compounds with improved activity against Mpro and the strategy developed for its generation can be applied to other pharmacological targets. Supported by PAPIIT-UNAM grant numbers IV200121 and IN206622.