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 () and can be applied to other pharmacological targets.