Sub-pocket-focused designing of tacrine derivatives as potential acetylcholinesterase inhibitors

Human acetylcholinesterase (hAChE) has a potential role in the management of acetylcholine, one of the neu-rotransmitters that modulate the overall activity of cholinergic system, AChE inhibitors have a greater impact in the therapeutics. Though the atomic structure of hAChE has been extensively studied, the precise active site geometry upon binding to different ligands are yet to be explored. In the present study, an extensive structural analysis of our recently reported hAChE-tacrine complex has carried out and revealed the presence of two prominent sub-pockets located at the vicinity of the hAChE active site. Structural bioinformatics assisted studies designed 132 putative sub-pockets focused tacrine derivatives (SPFTDs), their molecular docking, free energy estimations revealed that they are stronger than tacrine in terms of binding affinity. Our in vitro studies also supported the in silico findings, all these SPFTDs are having better potencies than tacrine. Cytotoxic nature of these SPFTDs on HepG2 and Neuro-2a cell lines, diminishes the possibilities for future in vivo studies. However, the identification of these sub pockets and the SPFTDs paved a new way to the future drug discovery especially since AChE is one of the promising and approved drug targets in treatment of AD drug discovery.

Automated summary

Human acetylcholinesterase (hAChE) plays a potential role in acetylcholine management and AChE inhibitors have a significant impact in therapeutics. This study explored the active site geometry of hAChE upon binding to different ligands and discovered two prominent sub-pockets near the active site. Structural bioinformatics analysis identified 132 putative sub-pockets focused tacrine derivatives (SPFTDs) that showed stronger binding affinity than tacrine. The identification of these sub-pockets and SPFTDs provides new possibilities for future drug discovery targeting AChE in the treatment of Alzheimer's disease (AD).