In-silico validation of novel therapeutic activities of withaferin a using molecular docking and dynamics studies

Withaferin A is a bioactive molecule of W. somnifera. We access its efficacy against various target proteins associated with Cancer, Type-II Diabetes and hypercholesterolemia using molecular docking. Although it's efficacy against some of these targets have been reported earlier, we validate each mechanism in order to report the most appropriate mechanism of action. We explain the anti-cancer activity of Withaferin A by inhibition of Mortalin (mtHsp70) and Nrf2 protein with binding energies -8.85 kcal/mol and -12.59 kcal/mol respectively. Similarly, the anti-diabetic activity could be explained by inhibition of alpha and betα-glucosidase with binding energies -6.44 and -4.43 kcal/mol respectively and the cholesterol reduction could be explained by its ability to inhibition of NPC1 and SRB1 with binding energies -5.73 and -7.16 kcal/mol respectively. The molecular dynamics of the apoprotein and the protein-ligand complex simulated for the best targets of each activity namely Nrf2 protein for anti-cancer, α-glucosidase for anti-diabetic and SR-B1 for anti-hypercholesterolemia activity indicated the formation of stable complexes due to low RMSD deviations, low RMSF fluctuations and low RG values after the docking simulation. Finally, an ADME + T (Adsorption, distribution, metabolism, excretion and toxicity) prediction on Withaferin A showed that it obeyed all the Lipinsky's rules and qualified the drug-like criteria. All these results validate that Withaferin A possess potential anti-cancer, anti-diabetic and cholesterol reducing properties. This is the first report that indicates the possibility of Withaferin A binding and inhibiting SR-B1 as a mechanism of its anti-hypercholesterolemia activity.