Towards more effective acetylcholinesterase inhibitors: a comprehensive modelling study based on human acetylcholinesterase protein-drug complex

Alzheimer's disease is a progressive neurodegenerative disorder and as the exact cause of the disease remains unknown, it still has no cure to date. Due to the fact that, until recently, there has been no crystal structure of human AChE in complex with drugs, researchers have had to use mainly Torpedo californica homologues which were later reported to have significantly different binding sites. In this study, an energy-based pharmacophore model that has the advantages of both ligand- and structure-based approaches was generated using hAChE crystal structures in complex with drugs. This model was validated utilizing several commonly used statistical measures such as the enrichment factor, BEDROC, RIE and AUAC. A huge database consisting of around 7 million compounds with approximately 150,000,000 conformations from 8 vendors was used in virtually screening workflow, in which Lipinski's filter and basic and precise docking algorithms were utilized. A rigorous MM-GBSA binding affinity calculation was also applied to accurately predict relative free energy that produced 361 hits. The selected top ranked 15 compounds were shown to have extra intermolecular interactions with hAChE which is an indication of a more stable complex and high binding affinity. The e-pharmacophore model and overall results obtained might be used for further experimental studies in designing the next generation of hAChE inhibitors. Communicated by Ramaswamy H. Sarma