Molecular interaction of investigational ligands with human brain acetylcholinesterase.

Alzheimer's disease, a neurodegenerative disorder continues to be an area of investigation by the international researchers' fraternity. Despite all the ongoing efforts, the effective set of promising cholinesterase inhibitors available in the market for patients' use is limited. Furthermore, the currently available drugs could provide only a palliative type of treatment instead of providing a complete cure or foolproof prevention. Hence, design/discovery of fresh drug molecules as acetylcholinesterase (AChE) inhibitors still remains an urgent requirement. The drug discovery platform, MCULE in the "structure-based virtual screening" (SBVS) mode was used for high throughput ligand screening of over five million structures targeted against the AChE catalytic site. A stepwise query was made for the SBVS input. The number of hits was narrowed down in consecutive succession via varied filtration criteria as AutoDock-Vina rankings, MCULE toxicity filtration, exclusion of ligands having less than four H-bond acceptors, filtration by ΔG cutoff, rule-of-five violation and SWISS ADME profiling. This was followed by holistic analysis of all the results, thereby leading to one promising ligand. The screened out drug molecule, MCULE-5872671137-0-1 exhibited a robust interaction with the AChE catalytic site involving 20 amino acid residues, an acceptable binding free energy of -10.2 kcal/mol in addition to a favorable SWISS ADME-profie showing no harmful effects on the human body. It can be carefully stated that the molecule, MCULE-5872671137-0-1, which is chemically (3S)-N-{4-[(4-chlorophenyl)sulfanyl]phenyl}-3-hydroxypyrrolidine-1-carboxamide could function as a significant "seed" ligand for future design of potent AChE inhibitors and/or novel neuro drugs built upon the seed-scaffold.