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

Aditi Srivastava; Rumana Ahmad; Irshad A Wani; Sahabjada Siddiqui; Kusum Yadav; Anchal Trivedi; Shivbrat Upadhyay; Ishrat Husain; Tanveer Ahamad; Shivanand S Dudhagi

doi:10.1007/s40203-023-00184-y

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

In Silico Pharmacol. 2024 Feb 27;12(1):14. doi: 10.1007/s40203-023-00184-y. eCollection 2024.

Affiliations

¹ Department of Biochemistry, Era's Lucknow Medical College & Hospital, Era University, Sarfarazganj, Hardoi Road, Lucknow, UP 226003 India.
² Department of Cardiology, Era University, Sarfarazganj, Hardoi Road, Lucknow, UP 226003 India.
³ Department of Biotechnology, Era University, Sarfarazganj, Hardoi Road, Lucknow, UP 226003 India.
⁴ Department of Biochemistry, University of Lucknow, Lucknow, UP 226007 India.
⁵ Plant Physiology Laboratory, CSIR-National Botanical Research Institute, Lucknow, UP 226001 India.

PMID: 38419919
PMCID: PMC10897645 (available on 2025-02-27)
DOI: 10.1007/s40203-023-00184-y

Abstract

Prevention from disease is presently the cornerstone of the fight against COVID-19. With the rapid emergence of novel SARS-CoV-2 variants, there is an urgent need for novel or repurposed agents to strengthen and fortify the immune system. Existing vaccines induce several systemic and local side-effects that can lead to severe consequences. Moreover, elevated cytokines in COVID-19 patients with cancer as co-morbidity represent a significant bottleneck in disease prognosis and therapy. Withania somnifera (WS) and its phytoconstituent(s) have immense untapped immunomodulatory and therapeutic potential and the anticancer potential of WS is well documented. To this effect, WS methanolic extract (WSME) was characterized using HPLC. Withanolides were identified as the major phytoconstituents. In vitro cytotoxicity of WSME was determined against human breast MDA-MB-231 and normal Vero cells using MTT assay. WSME displayed potent cytotoxicity against MDA-MB-231 cells (IC₅₀: 66 µg/mL) and no effect on Vero cells in the above range. MD simulations of Withanolide A with SARS-CoV-2 main protease and spike receptor-binding domain as well as Withanolide B with SARS-CoV spike glycoprotein and SARS-CoV-2 papain-like protease were performed using Schrödinger. 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 also displayed potent binding to pro-inflammatory markers viz. serum ferritin and IL-6. Thus, WS phytoconstituents have the potential to be tested further in vitro and in vivo as novel antiviral agents against COVID-19 patients having cancer as a co-morbidity.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-023-00184-y.

Keywords: In vitro cytotoxicity assay; MD simulation, SARS-CoV-2 variants; Papain-like protease; SARS-CoV-2 main protease; SARS-CoV-2 spike glycoprotein; Withania somnifera.

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