The rates at which drugs associate with and dissociate from their receptors directly impact drug efficacy and safety, but the molecular determinants of drug-receptor binding kinetics remain poorly understood, and the rational modulation of binding kinetics thus remains challenging.  Molecular dynamics simulations provide an increasingly powerful tool to elucidate the factors controlling binding kinetics at the atomic level.  In particular, recent advances in simulation speed and accuracy have made possible simulations in which certain drugs spontaneously associate with their receptors to achieve bound conformations that match crystal structures almost perfectly, allowing one to examine their binding process in full atomic detail.  I will describe several cases in which atomic-level simulations, together with complementary experimental data, have uncovered atomic-level determinants of drug binding kinetics, and I will discuss the implications of these findings for drug design.

Revealing molecular determinants of drug-receptor binding kinetics through atomic-level simulation

248th National Meeting (2014)

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