Identification of potential SARS-CoV-2 Mpro inhibitors from a Thai natural product database via interaction fingerprint-based virtual screening

The SARS-CoV-2 main protease (Mpro) is a promising target for coronavirus disease 2019 (COVID-19) therapy due to its high conservation and essential role in viral replication. In this study, 148 crystal structures of SARS-CoV-2 Mpro complexed with non-covalent inhibitors from the Protein Data Bank (PDB) were used to map the inhibitor binding site using protein-ligand interaction fingerprints (IFPs). The analysis revealed that the S2 binding site serves as a key region to anchor most non-covalent inhibitors. This mapping was used as a guide to virtually screen an in-house Thai natural product database for potential inhibitors of SARS-CoV-2 Mpro. Seven hit compounds were selected based on docking results, including pose quality, interaction profiles, and energetic criteria. Molecular dynamics simulations confirmed the stability of the SARS-CoV-2 Mpro-hit compound complexes, revealing that panduratin A (CPD3), deacetylmammea E/BA cyclo D (CPD4), and n-pentyl beta-carboline-1-propionate (CPD5) were particularly interesting virtual hits, as they consistently formed strong interactions with key residues at the S2 site through π-π, H-π, and hydrogen bonds.