In silico and in vitro studies on inhibitors for SARS-CoV-2 non-structural proteins with dual herbal combination of Withania somnifera with five rasayana herbs

Abstract

Being highly transmissible, severe acute respiratory syndrome coronavirus (SARS-CoV-2) has affected millions of people causing devastating global impact and has also not slowed down even after vaccination. The emerges of new strains has made more concerns than the original one. We need a new therapeutic approach against the disease. Our comprehensive in silico study investigates dual herbal combinatorial methanolic extracts of W. somnifera (W) alone and with P. emblica (P) (W:P/1:4) , T. sinensis (T) (W:T/1:4), B. monnieri (B) (W:B/1:1), O. basilicum (O) (W:O/1:4), A. racemosus (A) (W:A/4:1) for potential four phytochemicals as ligands docked with eight COVID-19 Nonstructural proteins (nsp)—main protease (PDB ID:6LU7), papain-like protease (6WUU), helicase ADP (2XZL), N7-methyltransferase (5C8S), endoribonuclease (6WLC), 2’O-methyltransferase (6WVN), RNA dependent RNA polymerase (6M71), and 3Cprotease (6YNQ) along with Remdesivir and Hydroxychloroquine. Ligands from W:P/1:4 showed remarkable docking score (−9.01 kcal/mol) 6M71-(8E,11E,14E)-eicosa-8,11,14-trienoicacidmethylester (EIS) and (−9.99 kcal/mol) 6YNQ-N-[(E)-[4-[(2-methoxydibenzofuran-3-yl)amino]-4-oxobutan-2-ylidene]amino] 4nitrobenzamide (MET). Further, MD simulations were studied for 100 ns and showed the complexes were flexible, stable in the binding pockets of the receptors, and MM-PBSA analysis determined high binding energy of −129.673 ± 15.284 and −134.594 ± 7.085 for 6M71-EIS (Asn⁴⁹⁶, Lys⁵⁷⁷, Arg⁵⁶⁹) and 6YNQ-MET (Cys¹⁴⁵, His⁴¹). Finally, in vitro JURKAT E6.1 cell lines treated with W:P/1:4 and W:O/1:4 methanolic extracts yielded 44.06 and 31.53 ng/mL levels for interferon alpha to counteract an external stimulus by establishing an antiviral state. Thus, nsp is targeted to design effective antiviral drugs for developing an effective therapeutic approach to combat viral RNA synthesis, processing, and suppression of host immunity.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Keywords:

• SARS-CoV-2
• Withania somnifera
• dual herbal combinatorial
• MD simulation
• interferon alpha

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Author contributions

BS and MS conceived the study and participated in its design and coordinated and helped to draft the manuscript. BS carried out the major part of the bioinformatics studies and in vitro analysis while JC performed Molecular dynamics simulation and energy calculations. BS and MS finally reviewed, revised, and edited the manuscript. All the authors read and approved the final manuscript.