The main protease (Mpro) of SARS-CoV-2 is a crucial enzyme needed for viral replication and has gathered significant interest in COVID-19 therapeutic research as a drug target. In the current study, we used an integrative approach that included computational methods to assess a curated collection of phytochemicals from plants as potential inhibitors of the Mpro. A library of 50 phytochemicals were screened through a docking program to identify the ones with the best binding affinity to the Mpro active site. The leading candidates were put through molecular dynamics (MD) simulations to examine the stabilities of protein-ligand complexes, and made use of MM-PBSA binding free energy calculations to quantify the strengths of bindings of the proteins and ligands. We also evaluated each phytochemical with ADMET profiling to detect whether they had drug-likeness and pharmacokinetic characteristics. Withanoside V and Kaempferol-3-O-rutinoside exhibited the best profiles of the lipophilicness, reversible bind of 3 for the catalytic residues (His41, Cys145), low predicted toxicity, and high GI absorptions. Overall, the data suggests that some phytochemicals may be effective leads for developing novel anti-SARS-CoV-2 antiviral agents. Furthermore, this work supports the ability of in silico methods to accelerate drug discovery based on natural products.
SARS-CoV-2, Main protease (Mpro), Phytochemicals, Molecular docking, Molecular dynamics simulation, MM-PBSA, ADMET, COVID-19, Natural product drug discovery
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