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

• Published in: Journal of biomolecular structure & dynamics Vol. 41; no. 17; pp. 8462 - 8471
• Main Authors: Thasweer, A. M., Renuka Devi, P., Thirunavukkarasu, Velusamy
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 22-11-2023
• Subjects: Cigarette smoke; molecular docking; molecular dynamics simulations; nicotine; NNK; NNN
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2022.2135022

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 α7nAChR and α4β2nAChR 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 α4β2nAChR 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 α7nAChR 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 α4β2nAChR and NNN with α7nAChR. 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