Unbinding Kinetics of Muscarinic M3 Receptor Antagonists Explained by Metadynamics Simulations.

ABSTRACT: The residence time (RT), the time for which a drug remains bound to its biological target, is a critical parameter for drug design. The prediction of this key kinetic property has been proven to be challenging and computationally demanding in the framework of atomistic simulations. In the present work, we setup and applied two distinct metadynamics protocols to estimate the RTs of muscarinic M3 receptor antagonists. In the first method, derived from the conformational flooding approach, the kinetics of unbinding is retrieved from a physics-based parameter known as the acceleration factor α (i.e., the running average over time of the potential deposited in the bound state). Such an approach is expected to recover the absolute RT value for a compound of interest. In the second method, known

SUBMITTER: Galvani F 

PROVIDER: S-EPMC10170513 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature