From pharmacophore predictions to pharmaceutical possibilities: an integrated approach to screen M3 selective muscarinic receptor antagonist.

Abstract

Muscarinic Acetylcholine Receptors (mAChR) are located in the central nervous system, peripheral nervous system, nerve synapses, and autonomic ganglia. They are coupled with G-proteins that regulate a range of functions like motor control, cardiac rhythm, smooth muscle contraction-relaxation, and glandular secretions. Muscarinic receptors have five subtypes that span from M₁ to M₅. Among them, M₃ mAChR has gained significant attention as per their involvement in irritable bowel syndrome, over active bladder, and chronic obstructive pulmonary disease. To identify M₃ selective antimuscarinic drugs using virtual screening, a five-feature three-dimensional quantitative structure-activity relationship pharmacophore model was generated with 0.962 correlation coefficient and 0.728 root mean square deviation. It was trained such that it passed Fischer's Randomization test at a 99% confidence level. The screened active molecules were calculated for pharmacokinetic properties to define drug-likeliness, and flexibly docked on receptors with a defined binding pocket to reach M₃ selective mAChR antagonists. For the leading candidates, calculating Molecular-Mechanics-Generalized-Born Surface Area binding free energy gave the optimal conformer for molecular dynamics studies. The generated frames showed molecule 45255447 (PubChemID) to be most stable at M₃ mAChR binding pocket and can be put forward for therapeutic potential through wet lab analysis.