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- W4384615983 endingPage "5272" @default.
- W4384615983 startingPage "5260" @default.
- W4384615983 abstract "Patient symptom relief is often heavily influenced by the residence time of the inhibitor-target complex. For the human muscarinic receptor 3 (hMR3), tiotropium is 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, the elucidation of the main factors determining the unbinding rates could help develop the next generation of antimuscarinic agents. Using our novel unbinding algorithm, we were able to investigate ligand dissociation from hMR3. The unbinding paths of tiotropium and two of its analogues, N-methylscopolamin and homatropine methylbromide, show a consistent qualitative mechanism and allow us to identify the structural bottleneck of the process. Furthermore, our machine learning-based analysis identified key roles of the ECL2/TM5 junction involved in the transition state. Additionally, our results point to relevant changes at the intracellular end of the TM6 helix leading to the ICL3 kinase domain, highlighting the closest residue L482. This residue is located right between two main protein binding sites involved in signal transduction for hMR3's activation and regulation. We also highlight key pharmacophores of tiotropium that play determining roles in the unbinding kinetics and could aid toward drug design and lead optimization." @default.
- W4384615983 created "2023-07-18" @default.
- W4384615983 creator A5002461166 @default.
- W4384615983 creator A5002860495 @default.
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- W4384615983 creator A5079404524 @default.
- W4384615983 creator A5082987481 @default.
- W4384615983 date "2023-07-17" @default.
- W4384615983 modified "2023-09-27" @default.
- W4384615983 title "Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor" @default.
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- W4384615983 doi "https://doi.org/10.1021/acs.jctc.3c00023" @default.