DE Shaw Research, New York, NY 10036, USA.
Drug Discov Today. 2013 Jul;18(13-14):667-73. doi: 10.1016/j.drudis.2013.02.007. Epub 2013 Feb 27.
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.
人们越来越认识到，药物与受体结合和解离的速率——结合动力学——直接影响药物的疗效和安全性。然而，药物-受体结合动力学的分子决定因素仍知之甚少，特别是与影响结合亲和力的众所周知的因素相比。因此，在先导化合物优化过程中合理地调节动力学仍然具有挑战性。我们回顾了一些被认为可以控制分子水平上药物-受体结合动力学的关键因素——分子大小、构象波动、静电相互作用和疏水效应，并讨论了几种合理设计具有所需结合动力学的药物的可能方法。
