Molecular determinants of drug–receptor binding kinetics

It is increasingly appreciated that the rates at which drugs associate with and dissociate from receptors — the binding kinetics — directly impact drug efficacy and safety. The molecular determinants of drug–receptor binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control drug–receptor binding kinetics at the molecular level — molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects — and discuss several possible approaches for the rational design of drugs with desired binding kinetics.

► Drug binding and unbinding rates impact efficacy and safety.
► The molecular determinants of binding kinetics are poorly understood.
► Determinants include molecular size, conformational fluctuations, electrostatic interactions, and hydrophobic effects.
► Recent experimental and computational advances facilitate elucidation of these molecular determinants.
► These determinants suggest several possible approaches to rational optimization of drug binding kinetics.