Molecular docking and dynamic simulation studies of α4β2 and α7 nicotinic acetylcholine receptors with tobacco smoke constituents nicotine, NNK and NNN

Smoking constitutes a major global health problem. As it triggers various health hazards including cancers, cardiac and pulmonary illness, it is imperative to understand the mechanism of action of various smoke constituents on our cellular processes. Various in vitro studies have compiled the affinity of cigarette smoke constituents on various nicotinic acetylcholine receptors (nAChRs). But the nature of the intermolecular interactions contributing to this affinity and the key amino acids in the receptor active sites involved in this are not investigated so far. Here, we are examining the interaction of alpha 7nAChR and alpha 4 beta 2nAChR on nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosornicotine (NNN), the physiologically significant constituents in smoke, through molecular docking and dynamics simulations study. The docking of alpha 4 beta 2nAChR structure with the ligands nicotine, NNK and NNN yielded docking scores of -41.45 kcal/mol, -59.28 kcal/mol and -54.60 kcal/mol, respectively, and that of alpha 7nAChR receptor molecule with the ligands yielded docking scores of -59.54 kcal/mol, -71.06 kcal/mol and -70.86 kcal/mol, respectively. The study showed that NNK exhibited the highest affinity with the ligands which was confirmed by dynamics simulation. But higher stability of interactions as surmised from Molecular dynamics simulations was found for nicotine with alpha 4 beta 2nAChR and NNN with alpha 7nAChR. The findings validate the in vitro studies comparing the affinities of these compounds. The study will be useful in formulating effective nAChR agonists to treat neurological disorders and antagonists for smoke deaddiction and improve health standards. Communicated by Ramaswamy H. Sarma