Targeting SARS-CoV-2 main protease: a pharmacophore and molecular modeling approach.

Context: The COVID-19 pandemic, driven by SARS-CoV-2, has had a profound impact on global health, with severe respiratory complications being a primary concern. The main protease (Mpro) of SARS-CoV-2 plays a critical role in viral replication, making it an attractive target for therapeutic intervention. This study aimed to identify potential Mpro inhibitors using an integrated computational approach. From an initial pool of 89,200 compounds in the ChemDiv database, a systematic screening process reduced the candidates to 735 through drug-like property predictions and pharmacophore-based virtual screening. Molecular docking against four co-crystal structures of the inhibitor/Mpro complex, followed by molecular dynamics (MD) simulations and binding free energy calculations, identified E912-0363 and G740-1003 as promising candidates with binding affinities comparable to nirmatrelvir. Extended 500-ns MD simulations further established E912-0363 as a highly promising Mpro inhibitor, supporting its potential for therapeutic development as a complementary or alternative treatment to nirmatrelvir.

Methods: Pharmacophore modeling and virtual screening were conducted using the ChemDiv database, reducing 89,200 compounds to 735 candidates based on drug-like property predictions. Molecular docking was performed against four SARS-CoV-2 Mpro co-crystal structures using AutoDock VinaXB and GOLD docking programs. The top five candidates (E912-0363, P635-0261, G740-1003, G069-0804, and 8602-0428) were subjected to 100-ns molecular dynamics (MD) simulations using the AMBER force field. Binding free energy calculations were performed using the MM/GBSA method. Extended 500-ns MD simulations were carried out for the most promising candidate, E912-0363, to evaluate its long-term stability and interaction with the Mpro binding site.