Amalgamation of experimental strategies, computational simulation, and computer-assisted-theoretical analysis to decipher the interaction of newly synthesized plumbagin-indole-3-propionic ester with cholinesterases.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are important target proteins to treat cognitive dysfunction in neurodegenerative diseases, such as Alzheimer's disease and Parkinson disease. Hence identification of inhibitors against these proteins is ever-growing. To get a foresight on the potential of a molecule that could be forwarded as a drug candidate, the combinations of bioinformatics [including molecular docking and molecular dynamics (MD) simulation], computer-assisted-theoretical analysis and in vitro strategy were employed to gain knowledge on interaction/inhibition of newly synthesized ester of plumbagin (PLU) and indole-3-propionic acid (IPA) called PLU-IPA with/against AChE and BChE. Density functional theory and ADME analysis revealed the non-toxicity and chemical reactivity gained by the molecule due to esterification and drug-likeness of PLU-IPA. PLU-IPA inhibited AChE and BChE in micromolar concentration through non-competitive mode. In molecular docking, PLU-IPA interacted with amino acids present in sub-pockets near the catalytic site, anionic site, and PAS of electric eel AChE (eAChE), human AChE (hAChE), and hBChE. Through computer-assisted-theoretical analysis, the importance of non-covalent interactions for the proper orientation of PLU-IPA within the active site gorge of AChE/BChE was understood. Further MD simulation results also confirmed the stable interaction of PLU-IPA with AChE/BChE.