Exploration of natural compounds with anti-SARS-CoV-2 activity via inhibition of SARS-CoV-2 M(pro)

Bharadwaj, Shiv; Dubey, Amit; Yadava, Umesh; Mishra, Sarad Kumar; Kang, Sang Gu; Dwivedi, Vivek Dhar

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a dreaded pandemic in lack of specific therapeutic agent. SARS-CoV-2 M(pro), an essential factor in viral pathogenesis, is recognized as a prospective therapeutic target in drug discovery against SARS-CoV-2. To tackle this pandemic, Food and Drug Administration-approved drugs are being screened against SARS-CoV-2 M(pro) via in silico and in vitro methods to detect the best conceivable drug candidates. However, identification of natural compounds with anti-SARS-CoV-2 M(pro) potential have been recommended as rapid and effective alternative for anti-SARS-CoV-2 therapeutic development. Thereof, a total of 653 natural compounds were identified against SARS-CoV-2 M(pro) from NP-lib database at MTi-OpenScreen webserver using virtual screening approach. Subsequently, top four potential compounds, i.e. 2,3-Dihydroamentoflavone (ZINC000043552589), Podocarpusflavon-B (ZINC000003594862), Rutin (ZINC000003947429) and Quercimeritrin 6”-O-L-arabinopyranoside (ZINC000070691536), and co-crystallized N3 inhibitor as reference ligand were considered for stringent molecular docking after geometry optimization by DFT method. Each compound exhibited substantial docking energy >−12 kcal/mol and molecular contacts with essential residues, including catalytic dyad (His(41) and Cys(145)) and substrate binding residues, in the active pocket of SARS-CoV-2 M(pro) against N3 inhibitor. The screened compounds were further scrutinized via absorption, distribution, metabolism, and excretion - toxicity (ADMET), quantum chemical calculations, combinatorial molecular simulations and hybrid QM/MM approaches. Convincingly, collected results support the potent compounds for druglikeness and strong binding affinity with the catalytic pocket of SARS-CoV-2 M(pro). Hence, selected compounds are advocated as potential inhibitors of SARS-CoV-2 M(pro) and can be utilized in drug development against SARS-CoV-2 infection.