Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

• DOI: 10.1021/acs.jctc.3c00023
• Publication Date: 2023-07-17T14:39:29Z
• Authors: Pedro J. Buigues; Sascha Gehrke; Magd Badaoui; Balint Dudas; Gaurav Mandana; Tianyun Qi; Giovanni Bottegoni; Edina Rosta
• Keywords: Computational chemistry; Pulmonary Disease, Chronic Obstructive; Chemical structure; Receptors; Humans; Muscarinic Antagonists; Molecules; Tiotropium Bromide; Ligands; Receptors, Muscarinic; 3. Good health; Bronchodilator Agents

Patient symptom relief is often heavily influenced by the residence time of inhibitor-target complex. For human muscarinic receptor 3 (hMR3), tiotropium a long-acting bronchodilator used in conditions such as asthma or chronic obstructive pulmonary disease (COPD). The mechanistic insights into this inhibitor remain unclear; specifically, elucidation main factors determining unbinding rates could help develop next generation antimuscarinic agents. Using our novel algorithm, we were able to investigate ligand dissociation from hMR3. paths and two its analogues, N-methylscopolamin homatropine methylbromide, show consistent qualitative mechanism allow us identify structural bottleneck process. Furthermore, machine learning-based analysis identified key roles ECL2/TM5 junction involved transition state. Additionally, results point relevant changes at intracellular end TM6 helix leading ICL3 kinase domain, highlighting closest residue L482. This located right between protein binding sites signal transduction for hMR3's activation regulation. We also highlight pharmacophores that play kinetics aid toward drug design lead optimization.