<i>In-silico</i> validation of novel therapeutic activities of withaferin a using molecular docking and dynamics studies
Creators: name: Ulhas, Rutwick Surya
name: Malaviya, Alok
Publisher: name: Taylor & Francis
Year: 2022
Subjects: subject: Biophysics
subject: Biochemistry
subject: 29999 Physical Sciences not elsewhere classified
subject: FOS: Physical sciences
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: Immunology
subject: FOS: Clinical medicine
subject: 69999 Biological Sciences not elsewhere classified
subject: Developmental Biology

description: Withaferin A is a bioactive molecule of <i>W. somnifera.</i> 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. This paper validates various mechanisms proposed for the anti-cancer, anti-diabetic and anti-hypercholesterolemic properties of Withaferin A obtained from <i>Withania somnifera</i> 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