Natural-like products as potential SARS-CoV-2 M inhibitors: drug discovery.

In December 2019, a COVID-19 epidemic was discovered in Wuhan, China, and since has disseminated around the world impacting human health for millions. Herein, drug discovery approaches have been utilized to identify potential natural products (NPs) as Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) main protease (M) inhibitors. The MolPort database that contains over 100,000 NPs was screened and filtered using molecular docking techniques. Based on calculated docking scores, the top 5,000 NPs/natural-like products (NLPs) were selected and subjected to molecular dynamics (MD) simulations followed by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. Combined 50 ns MD simulations and MM-GBSA calculations revealed nine potent NLPs with binding affinities (Δ) > -48.0 kcal/mol. Interestingly, among the identified NLPs, four bis([1,3]dioxolo)pyran-5-carboxamide derivatives showed Δ > -56.0 kcal/mol, forming essential short hydrogen bonds with HIS163 and GLY143 amino acids via dioxolane oxygen atoms. Structural and energetic analyses over 50 ns MD simulation demonstrated NLP-M complex stability. Drug-likeness predictions revealed the prospects of the identified NLPs as potential drug candidates. The findings are expected to provide a novel contribution to the field of COVID-19 drug discovery.Communicated by Ramaswamy H. Sarma.