Molecular interaction of anti-cancer ligands with human brain acetylcholinesterase

There are a significant number of cases whereby cancer patients belonging to the old age group additionally suffer from cognition decline (a hallmark feature of Alzheimer's disease). Hence, it is understandable that it would be a boon if certain drug molecules could provide health benefits to a patient suffering from cancer as well as Alzheimer's disease. The objective of the work was to identify anticancer molecule(s) whose chemical-skeleton could be used as 'seed' for future design of dual-acting drugs against Alzheimer's disease and cancer. The study employed criterion-based search, docking, SWISS-ADME-profiling, ▵ASA-calculations, molecular-overlay and 'MoMA'-simulation to query possible binding of selected anticancer molecules with human brain acetylcholinesterase (AChE). Molecular interactions of all of the top ranking ligands were analyzed. 'BOILED-egg' model was employed to query brain-penetration of the ligands. A detailed molecular-simulation-analysis was performed. Snapshots of different stages of dynamic molecular interactions (selected from 254 pdb files) were captured by MoMA LigPath, a robotics inspired simulation algorithm. The study concluded that chemical skeletons of 'Niraparib' and 'Ponatinib' might be used as 'seed(s)' for design of such drugs. If successfully materialized in future, this approach could decrease the total number of daily pills that an old patient needs to take. Furthermore, novel anticancer drugs could be synthesized that do not inhibit AChE (e.g. by removal/modification of moieties that are crucial to binding of anticancer drug to AChE) even if those happen to be 'Blood Brain Barrier'-permeable. Alternatively, fresh AChE-inhibitors could be designed based on the scaffolds of the aforementioned anticancer drugs.Communicated by Ramaswamy H. Sarma.