Deciphering the Withania somnifera alkaloids potential for cure of neurodegenerative disease: an in-silico study

Abstract

Abstract This study investigates the interaction of alkaloids of Withania somnifera with Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), an enzyme implicated in the pathology of various neurodegenerative diseases. Initially, the Withania somnifera phytochemicals were optimised then molecular dockings were performed. The molecular docking results identified key interactions between these alkaloids and active sites of the enzyme. Several alkaloids from Withania somnifera exhibited better binding affinities to GAPDH such as Withanolides G, I, and K with binding affinity of -10.1, -10, and − 10 kcal/mol. The binding orientations and stability of these withanolide derivatives complexes GAPDH were investigated through comprehensive molecular dynamics simulations over 100 nanoseconds. The molecular dynamics simulations revealed stable interactions over the simulation period, suggesting a strong binding propensity. Furthermore, we determined the free energy binding profiles with GAPDH using BAR method, whichresulted in improved free energybinding forWithanolide-G and I.The results envisage that withanolides showed excellent bindings and stable interaction with the GAPDH, making them an effective therapeutic agent. The current study providesan excellent platform for developing new therapeutic agents derived from Withania somniferaagainst neurodegenerative diseasesassociated with GAPDH malfunction. These novel results open novel avenues for future research in drug discovery, particularly in developing novel treatments for Alzheimer’s, Parkinson’s, and other neurodegenerative diseases where GAPDH dysfunction plays crucial roles.Furthermore, experimental validation is required to validate the results of the current study.

Keywords

• GAPDH
• Withania somnifera
• Alkaloids
• Molecular dockings
• MD simulations
• Free Energy Perturbation