Computational Investigation on the Efficiency of Small Molecule Inhibitors Identified from Indian Spices against SARS-CoV-2 Mpro

Recently, small compounds from Indian spices (Carnosol, Arjunglucoside-I, and Rosmanol) have been identified as SARS-CoV-2 main protease (Mpro) inhibitors. The structural dynamics and characteristic features of binding of these small molecules to the SARS-CoV-2 Mpro are not well understood. Here, we have constructed the potential of mean force (PMF) for dissociating Mpro-small molecule inhibitor complexes from the umbrella sampling simulations using the weighted histogram analysis method. Mpro-small molecule inhibitor complexes exhibited relatively higher dissociation energy values than the alpha-ketoamide-Mpro complex (positive control) from the PMF calculations. We found that binding affinity between protein and ligand is higher in Mpro-Arjunglucoside-I complex [Delta G(bind) = 19.74 kcal mol(-1) from MM-GBSA and Delta G(bind) = -9.13 kcal mol(-1) from MM-PBSA] than in other three SARS-CoV-2 small molecule complexes. The MM-GBSA/MM-PBSA calculations revealed that the small molecule inhibitors studied in this work have substantially higher binding affinity for Mpro. We found the residues present in SARS-CoV-2 Mpro's binding pocket contributed the most binding free energy to SARS-CoV-2 Mpro-small molecule interactions. Our findings emphasize the structural and binding features of the identified small molecule inhibitors with SARS-CoV-2 Mpro, which could be relevant in developing therapeutic candidates to combat SARS-CoV-2.