从噻托溴铵谈药物与受体的结合动力学

Drug-receptor binding kinetics: tiotropium bromide as an example

在新药研发的早期阶段,除了评价化合物对靶标的亲和力和选择性外,还有一个重要参数,即复合物的动力学性质。这是一个与体内药效和安全性密切相关的活性特征。新药研究中化合物的复合物离解常数(K d)或IC50值是在封闭系统的平衡状态下测定的,而药物在体内处于开放系统,浓度和环境在不断地变化,K d或IC50不能够完全反映体内药物与靶标结合的实际状态。复合物的离解速率不受游离药物浓度的影响,具有慢离解速率即长驻留时间的药物对药理作用的持续时间、选择性作用和安全性有重要关联性。本文简要地叙述药物结合动力学原理和对药物作用的影响,并用一些实例说明结合动力学在新药创制与研究中的意义。

Biding kinetics investigation, in addition to thermodynamic evaluation of target affinity and selectivity, is of importance during the early stage of drug discovery, because ligand-target complex correlates to in vivo efficacy, selectivity as well as safety. Association rate （kon） and dissociation rate （koff） of a ligand-target complex should be measured during the early stage of drug innovation. The Kd or IC50 values of compounds are determined in a closed system and equilibrium condition. Drug molecules in vivo, however, are in a constantly changing open system. In vitro Kd or IC50 does not necessarily reflect the actual binding condition of a drug to its in vivo target. The dissociation rate of a drug-target complex is not influenced by the concentration of the free drug. Drugs with small koff values （i. e. long residence time） play important roles in the maintenance of duration time, selectivity, and safety. This mini-review concisely describes the principle of binding kinetics and the influence of structural features upon association and dissociation rates, as well as a few examples to illustrate the significance of binding kinetics in drug research and discovery.