Kherachi_2026_In.Silico.Pharmacol_14_111

Alzheimer's disease (AD) is a condition that mostly affects individuals in the latter stages of life. Due to the importance of inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in improving cholinergic transmission in the brain, both enzymes were targeted to provide a direct therapeutic approach against AD. In this study, we examined a novel set of derivatives of 4-(Trifluoromethyl)benzohydrazide, which have been identified for their potential to prevent the progression of the aforementioned illness. In this study, various computational techniques, including molecular docking, molecular dynamics (MD) simulations, bioisosteric replacement, and ADMET predictions, were utilized to discover potential inhibitors of AChE and BuChE from a set of twenty-five compound derivatives. The most promising inhibitors for each target, namely 2 s for AChE (- 7.674 kcal/mol) and 2r for BuChE (- 6.144 kcal/mol), along with their isosteres, were identified based on their high docking scores. Furthermore, the stability of these inhibitors was confirmed through MD simulation, and they exhibited favorable drug-likeness properties and safety profiles. Hence, it is essential to do more research to advance their potential as pharmaceutical agents for the treatment of AD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00605-8.