Unbinding Kinetics of Muscarinic M3 Receptor Antagonists Explained by Metadynamics Simulations

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 as the tMETA‑D approach, a qualitative estimation
of the RT is given by the time of simulation required to drive the
ligand from the binding site to the solvent bulk. This approach has
been developed to reproduce the change of experimental RTs for compounds
targeting the same target. Our analysis shows that both computational
protocols are able to rank compounds in agreement with their experimental
RTs. Quantitative structure–kinetics relationship (SKR) models
can be identified and employed to predict the impact of a chemical
modification on the experimental RT once a calibration study has been
performed.