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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.