Withanolides from Withania somnifera as an immunity booster and their therapeutic options against COVID-19

Abstract

Traditionally, Withania somnifera is widely used as an immune booster, anti-viral, and for multiple medicinal purposes. The present study investigated the withanolides as an immune booster and antiviral agents against the coronavirus-19. Withanolides from Withania somnifera were retrieved from the open-source database, their targets were predicted using DIGEP-Pred, and the protein-protein interaction was evaluated. The drug-likeness score and intestinal absorptivity of each compound were also predicted. The network of compounds, proteins, and modulated pathways was constructed using Cytoscape, and docking was performed using autodock4.0, and selected protein-ligand complexes were subjected to 100 ns Molecular Dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-GBSA method. Withanolide_Q was predicted to modulate the highest number of proteins, showed human intestinal absorption, and was predicted for the highest drug-likeness score. Similarly, combined network interaction identified Withanolide_Q to target the highest number of proteins; RAC1 was majorly targeted, and fluid shear stress and atherosclerosis associated pathway were chiefly regulated. Similarly, Withanolide_D and Withanolide_G were predicted to have a better binding affinity with PLpro, Withanolide_M with 3CLpro, and Withanolide_M with spike protein based on binding energy and number of hydrogen bond interactions. MD studies suggested Withanoside_I with the highest binding free energy (DG bind -31.56 kcal/mol) as the most promising inhibitor. Among multiple withanolides from W. somnifera, Withanolide_D, Withanolide_G, Withanolide_M, and Withanolide_Q were predicted as the lead hits based on drug-likeness score, modulated proteins, and docking score to boost the immune system and inhibit the COVID-19 infection, which could primarily act against COVID-19. HIGHLIGHTSWithanolides are immunity boosters. Withanolides are a group of bio-actives with potential anti-viral properties. Withanolide_G, Withanolide_I, and Withanolide_M from Withania somnifera showed the highest binding affinity with PLpro, 3CLpro, and spike protein, respectively. Withanolides from Withania somnifera holds promising anti-viral efficacy against COVID-19.

In Silico Evaluation of Iranian Medicinal Plant Phytoconstituents as Inhibitors against Main Protease and the Receptor-Binding Domain of SARS-CoV-2

“…In one study, withanolide Q was predicted to modulate the highest number of proteins, showed positive human intestinal absorption, and had the highest drug-likeness score. Similarly, withanolide D and withanolide G were predicted to have better binding affinity with SARS-CoV-2 papain-like cysteine protease (PL pro ), withanolide M with M pro , and withanolide M with spike protein based on binding energy and the number of hydrogen bond interactions [ 44 ]. In the present study, withanone (−7.7 (kcal/mol) against RBD), withanolide A (−8.6 (kcal/mol) against M pro ), and withanolide G (−7.4 (kcal/mol) against RBD) showed the best binding affinity to receptors among the withanolides ( Table 1 ).…”

Rac1, A Potential Target for Tumor Therapy

“…PI3K activates immunity by up-regulating IL-10 and inhibiting proinflammatory cytokines, possibly through the regulation of Rac1 protein (162). Withanolides, as immunopotentiators and antiviral agents against COVID -19, may play a role by targeting the Rac1 protein (163). Compared with Rac1 WT, melanoma cells with Rac1(P29S) mutations express high levels of PD-L1 and therefore have the ability to evade immune surveillance (164).…”

Withania somnifera (L.) Dunal: Opportunity for Clinical Repurposing in COVID-19 Management

“…A study carried out by our team predicted the potential of withacoagin and withanolide B to block viral spike protein and RdRp enzyme with a high binding affinity (Borse et al, 2020). Moreover, many recent virtual screening studies reported the potential of withanolides to inhibit SARS-CoV-2 proteins with a high binding affinity (Khanal et al, 2021) (Srivastava et al, 2020) (Parida et al, 2020) (Shree et al, 2020) (Tripathi. M. K. et al, 2020) (Chikhale et al, 2020).…”