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

Abstract

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.

Graphical Abstract

Highlights

• This paper validates various mechanisms proposed for the anti-cancer, anti-diabetic and anti-hypercholesterolemic properties of Withaferin A obtained from Withania somnifera L. Dunal

• The 3D structure of Withaferin A was docked to the suitable target proteins using Molecular docking server (AutoDock algorithm) and the binding energies were assessed. Molecular dynamics simulations of the protein ligand complex were also studied and found to indicated stable binding

• Additionally, the ligand was accessed to be drug-like in terms of its ADME + T predictions

• Inhibition of SR-B1 and NPC-1 as potential anti-hypercholesterolemic mechanism of Withaferin A was reported for the first time in this paper

Communicated by Ramaswamy H. Sarma

Keywords:

• Anti-cancer
• anti-diabetic
• cholesterol reduction
• docking
• Withaferin A
• W. somnifera

Acknowledgements

We would like to thank Christ (Deemed to be University) for providing support and encouragement for this research. We also thank Prof T. Usha for her help and feedback during preparation of this MS.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was carried out as a part of RGS/F Project (GRD Number - 894) funded by Vision Group on Science and Technology (VGST), Department of Electronics, IT, BT and S&T, Government of Karnataka.