Neurodegenerative diseases have gained focus in recent years as most of the drugs available for treatment do not provide a complete cure rather, they assist the patient in good living. One of the most common neurodegenerative diseases in old individuals is Alzheimer's disease (AD) against which only limited resources are available to treat the patients such as donepezil. Molecules responsible for the manifestation of disease are the potential targets for the discovery of novel inhibitors.

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... cholinesterase (AChE) is an enzyme found in the brain and is responsible for the breakdown of acetylcholine. AChE inhibition may lead to slow down or stop the degeneration of neurons, therefore a variety of inhibitors have been discovered but these inhibitors only decrease the rate of neuron degeneracy which in turn provides ample scope for the discovery of new inhibitors. MCULE tool was used to screen out millions of compounds and further various criteria were applied to find out the best plausible therapeutic molecule. A toxicity filter was applied so that only those compounds are selected which are non-toxic. AutoDock-Vina rankings, leaving out ligands having less than four H-bond acceptors, as well as blood-brain barrier impermeability, filtration by G cutoff, rule-of-five (RO5) violation and SWISS ADME profiling, were used to narrow down hits to find out possible binding of selected molecules with human brain AChE. A holistic analysis of the compounds resulted in further screening of the compounds. Various computational tools such as CASTp3.0, MCULE, SWISS ADME, etc., were used to examine and screen out millions of compounds to narrow down the search for potential AChE inhibitor which eventually resulted in selecting the 'top molecule', namely; (4Z)-4-[(4-fluorophenyl)hydrazinylidene]-5-methyl-2-phenylpyrazol-3-one with MCULE id MCULE-9685671672, the selected compound was found to display a robust binding with human AChE through 20 amino acid residues (G: -10.7 kcal/mol) while 7 of these residues were same as those displayed by 'Donepezil binding interactions'. It very easily passed through all major drug screen filters, including the 'toxicity checker'. Post MD analysis depicts MCULE-9685671672 is more stable in comparison to Donepezil with a G of -10.7 kcal/mol satisfying adequate ADME and molecular dynamic features for further in vitro and in vivo validation in the context of Alzheimer's disease. The stability of the best ligand hit was assessed through MD simulation of 50 ns duration.