Steroidal lactones from Withania somnifera effectively target Beta, Gamma, Delta and Omicron variants of SARS-CoV-2 and reveal a decreased susceptibility to viral infection and perpetuation: A Polypharmacology Approach

Abstract Prevention from disease is presently the cornerstone of the fight against COVID-19. With the rapid emergence of novel variants of SARS-CoV-2 viz . B.1.1.7 (UK), B.1.351 (South Africa), P.1 (Brazil), delta variant B.1.617.2 (India) and the recently emerged Omicron variant B.1.1.529 (South Africa), there is an urgent need for novel prophylactic agents that have the ability to strengthen and fortify the immune system. To this effect, Withania somnifera (WS) and its phytoconstituent(s) have immense untapped immunomodulatory and therapeutic potential. The in vitro and in vivo anticancer potential of WS is well documented. Recent studies have indicated that the prognosis of COVID patients having cancer as a co-morbidity is poor as the viral infection has been shown to upregulate epithelial-to-mesenchymal transition (EMT) and promote metastasis. WS methanolic extract (WSME) was characterized using HPLC and Withaferin A as standard. In vitro cytotoxicity of WSME was determined against cancer (MDA-MB-231) and normal (Vero) cell lines by MTT assay. Molecular dynamics simulations of Withanolide A with SARS-CoV-2 main protease, spike receptor-binding domain and Withanolide B with SARS-CoV spike glycoprotein and SARS-CoV-2 papain-like protease were performed using Schrödinger. Withaferin A was identified in WSME. WSME displayed potent cytotoxicity against cancer cells. Stability of complexes followed the order 6M0J-Withanolide A>6W9C-Withnaolide B>5WRG-Withanolide B>6LU7-Withanolide A. Maximum stable interaction(s) were observed between Withanolides A and B with SARS-CoV-2 and SARS-CoV spike glycoproteins, respectively. Withanolides A and B have the potential to be tested further in vitro and in vivo as novel antiviral agents against SARS-CoV-2 and SARS-CoV.