Back to Search
Start Over
Sub-pocket-focused designing of tacrine derivatives as potential acetylcholinesterase inhibitors.
- Source :
-
Computers in biology and medicine [Comput Biol Med] 2023 Mar; Vol. 155, pp. 106666. Date of Electronic Publication: 2023 Feb 11. - Publication Year :
- 2023
-
Abstract
- 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.<br />Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose.<br /> (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Subjects :
- Humans
Cholinesterase Inhibitors chemistry
Cholinesterase Inhibitors pharmacology
Cholinesterase Inhibitors therapeutic use
Acetylcholinesterase chemistry
Acetylcholinesterase metabolism
Acetylcholinesterase therapeutic use
Molecular Docking Simulation
Structure-Activity Relationship
Tacrine pharmacology
Tacrine therapeutic use
Alzheimer Disease metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0534
- Volume :
- 155
- Database :
- MEDLINE
- Journal :
- Computers in biology and medicine
- Publication Type :
- Academic Journal
- Accession number :
- 36841058
- Full Text :
- https://doi.org/10.1016/j.compbiomed.2023.106666