New perspectives on the computational characterization of the kinetics of binding-unbinding in drug design: implications for novel therapies

Abstract

The efficiency and the propensity of a drug to be bound to its target protein have been inseparable concepts for decades now. The correlation between the pharmacological activity and the binding affinity has been the first rule to design and optimize a new drug rationally. However, this argument does not prove to be infallible when the results of in vivo assays have to be confronted. Only recently, we understand that other magnitudes as the kinetic rates of binding and unbinding, or the mean residence time of the complex drug-protein, are equally relevant to draw a more accurate model of the mechanism of action of a drug. It is in this scenario where new computational techniques to simulate the all-atom dynamics of the biomolecular system find its valuable place on the challenge of designing new molecules for more effective and less toxic therapies.