Affinity of nicotinoids to a model nicotinic acetylcholine receptor (nAChR) binding pocket in the human brain

The binding affinity of nicotinoids to the binding residues of the a4b2 variant of the nicotinic acetylcholine receptor (nAChR) was identified as a strong predictor of the nicotinoid's addictive character. Using ab-initio calculations for model binding pockets of increasing size comprising of 3, 6, and 14 amino acids (3AA, 6AA, and 14AA) that are derived from the crystal structure, the differences in binding affinity of 6 nicotinoids, namely nicotine (NIC), nornicotine (NOR), anabasine (ANB), anatabine (ANT), myosmine (MYO), and cotinine (COT) were correlated to their previously reported doses required for increases in intracranial self-stimulation (ICSS) thresholds, a metric for addictive characteristics. By employing the many body decomposition, differences in the binding affinities of the various nicotinoids could be attributed mainly to the proton exchange energy between the Pyridine and non-Pyridine rings of the nicotinoids and the interactions between them and a handful of proximal amino acids, namely Typ156, Typb57, Tyr100, and Tyr204. Interactions between the guest nicotinoid and the amino acids of the binding pocket were found to be mainly classical in nature, except for those between the nicotinoid and Typ156. The larger pockets were found to model binding structures more accurately and predicted the addictive character of all nicotinoids. Smaller models, which are more computationally feasible, would only predict the addictive character of nicotinoids similar to that of nicotine. The present study identifies the binding affinity of the guest nicotinoid to the host binding pocket as a strong descriptor of the nicotinoid's addiction potential and as such it can be employed as a fast screening technique for the potential addiction of nicotine analogs.