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

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 M to M. Among them, M mAChR has gained significant attention as per their involvement in irritable bowel syndrome, over active bladder, and chronic obstructive pulmonary disease. To identify M 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 M 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 M mAChR binding pocket and can be put forward for therapeutic potential through wet lab analysis.