Molecular Docking and Dynamics Simulation Reveal Withanolides As Potent Antivirals Against Dengue Virus

The prevalence of dengue remains a significant global threat to public health with millions of infections reported annually due to the lack of effective treatment options. Natural resources such as plants contain phytochemicals with desirable therapeutic effects. For instance, the Indian ginseng, Withania somnifera L. (Solanaceae), contains steroidal lactones, saponins, glycosides, and alkaloids which possessed antiviral activities against various viruses. In this study, docking analysis of seven compounds and phytochemicals were performed against the structural and non-structural (NS) proteins of all four dengue virus (DENV) serotypes as well as host cell receptors such as DC-SIGN and CLEC5A. Withanolide A (L5) was selected as the best inhibitor with high binding affinities towards ten targets consisting of DENV structural and NS proteins as well as the CLEC5A receptor. L5 also showed a fair stability with DENV1, DENV2, and DENV3 over a time span of 100 ns via molecular dynamics simulation. L5 demonstrated good drug-likeness properties, a moderate bioavailability score of 0.55, and is predicted to have high gastrointestinal absorptivity. The data from this in silico study revealed the potential of withanolide A to be further developed as an antiviral against dengue. This is the first study to report the in silico analyses of phytochemicals derived from W. somnifera L. (Solanaceae) against the viral proteins of DENV1 to 4 and their respective host cell receptors.