Molecular Dynamics Simulations and Kinetic Measurements to Estimate and Predict Protein–Ligand Residence Times

Ligand–target
residence time is emerging as a key drug discovery
parameter because it can reliably predict drug efficacy in vivo. Experimental
approaches to binding and unbinding kinetics are nowadays available,
but we still lack reliable computational tools for predicting kinetics
and residence time. Most attempts have been based on brute-force molecular
dynamics (MD) simulations, which are CPU-demanding and not yet particularly
accurate. We recently reported a new scaled-MD-based protocol, which
showed potential for residence time prediction in drug discovery.
Here, we further challenged our procedure’s predictive ability
by applying our methodology to a series of glucokinase activators
that could be useful for treating type 2 diabetes mellitus. We combined
scaled MD with experimental kinetics measurements and X-ray crystallography,
promptly checking the protocol’s reliability by directly comparing
computational predictions and experimental measures. The good agreement
highlights the potential of our scaled-MD-based approach as an innovative
method for computationally estimating and predicting drug residence
times.