Search

Emergence of COVID-19 and thereafter intensive research on bioactive natural compounds against SARS-CoV-2, identified a large number of phytochemicals (i.e., plants-derived) and mycochemicals (i.e., fungi-derived) as potential inhibitors with proven antiviral properties against SARS-CoV-2, but there are no comparative study on the reported compounds. A comparative study among the previously identified/reported main protease (Mpro) inhibitors of SARS-CoV-2 can lead to the most potent compound that eventually helps to make an effective drug lead against SARS-CoV-2. Through manual literature curation, we selected 57 potential bioactive compounds and screened them against Mpro protein of SARS-CoV-2. A series of in silico screening such as binding affinity, drug-like properties, pharmacokinetic, physicochemical, and ADMET studies identified top ten compounds as potential Mpro inhibitors. Further, docking studies prioritized the top two compounds namely Norquinadoline A and Quinadoline B, based on their predicted affinity for the target protein. Binding free energy calculations further emphasized them as top candidates for effective Mpro inhibitors that hold promise for drug development against COVID-19. In-depth molecular dynamics studies and MM/PBSA analysis culminated in the recognition of Norquinadoline A as the most potent Mpro inhibitor of SARS-CoV-2. Thus, Norquinadoline A can be used as lead compound in further drug discovery process after in vitro and in vivo experimental studies.

ABSTRACT PRS17, a variant of human immunodeficiency virus type I protease (HIV-1 PR), has 17 mutated residues showing high levels of multidrug resistance. To describe the effects of these mutated residues on the dynamic properties and the binding mechanism of PR with substrate and inhibitor, focused on six systems (two complexes of WT PR and PRS17 with inhibitor Darunavir (DRV), two complexes of WT PR and PRS17 with substrate analogue CA-p2, two unligand WT PR and PRS17), we performed multiple molecular dynamics (MD) simulations combined with MM-PBSA and solvated interaction energy (SIE) methods. For both the unligand PRs and ligand-PR complexes, the results from simulations revealed 17 mutated residues alter the flap-flap distance, the distance from flap regions to catalytic sites, and the curling degree of the flap tips. These mutated residues changed the flexibility of the flap region in PR, and thus affected its binding energy with DRV and CA-p2, resulting in differences in sensitivity. Hydrophobic cavity makes an important contribution to the binding of PR and ligands. And most noticeable of all, the binding of the guanidine group in CA-p2 and Arg8’ of PRS17 is useful for increasing their binding ability. These results have important guidance for the further design of drugs against multidrug resistant PR. IMPORTANCE Developing effective anti-HIV inhibitors is the current requirement to cope with the emergence of the resistance of mutants. Compared with the experiments, MD simulations along with energy calculations help reduce the time and cost of designing new inhibitors. Based on our simulation results, we propose two factors that may help design effective inhibitors against HIV-1 PR: (i) importance of hydrophobic cavity, and (ii) introduction of polar groups similar to the guanidine group.