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 neurotransmitters 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. [Display omitted] •Human acetylcholinesterase (hAChE) is one of the widely studied drug targets for Alzheimer's disease (AD), myasthenia gravis and glaucoma.•Out of the four FDA approved AD drugs, three are hAChE inhibitors, indicating the important role of hAChE in the treatment of AD.•In our previous studies the X-ray crystal structure of hAChE-tacrine complex has deduced.•In the present study, an extensive structural analysis of the previously reported hAChE crystal structure has been carried out.•Two prominent sub-pockets (named as SP1 and SP2) located at the vicinity of the active site of hAChE has been identified.•Structural bioinformatics assisted studies designed 132 putative sub-pockets focused tacrine derivatives (SPFTDs).•6-promising SPFTDs were synthesized for preliminary studies.•In the in vitro studies, we found SPFTDs have better potencies than tacrine.•Cytotoxic nature of these SPFTDs on HepG2 and Neuro-2a cell lines, diminishes the possibilities for future in vivo studies.•The identification of these sub pockets on hAChE and the SPFTDs paved a new way to the future AD drug discovery.