Kinetic and Thermodynamic Assessment of Binding of Serotonin Transporter Inhibitors
Kinetic and Thermodynamic Assessment of Binding of Serotonin Transporter Inhibitors
复制标题
DOI：
10.1124/jpet.108.142307
复制
发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Milla, Marcos E.
中科院分区：
文献类型：
--
作者：
Martin, Renee S.;Henningsen, Robert A.;Milla, Marcos E.
几种5-羟色胺再摄取抑制剂在临床上用于治疗抑郁症和焦虑症。然而，到目前为止，这些配体的药理学差异主要集中在它们对5-羟色胺转运蛋白的平衡结合亲和力上。本研究采用放射性配体结合试验与[H-3] S-西酞普兰，以确定在多个温度下的平衡和动力学速率常数的抗抑郁药结合模式的新的面貌。在26 ℃下观察到的解离速率常数落入一个狭窄的范围内的所有分子。相反，缔合速率常数一般随着平衡结合亲和力的增加而降低。与此一致，S-西酞普兰缔合的测定活化能相对较大（19.5 kcal . mol（-1）），表明配体结合后构象发生变化。对于大多数药物，包括西酞普兰，通过范特霍夫分析确定对反应能量学的焓（Δ H-O）和熵（-T Δ S-O）贡献大致相等（25-75% Δ G（O））并且与药物的极性表面积相关（对于焓为正相关）。然而，药物氟伏沙明的结合主要是熵驱动的。当这些数据被认为是在这些配体的物理化学性质的上下文中，可以提出两种不同的结合模式。西酞普兰型结合模式可能使用极性结合口袋，其允许配体和受体之间的带电或极性相互作用，由于脱水而具有相对较小的焓损失。氟伏沙明型结合模式由在将疏水配体部分埋入结合口袋中时释放的能量提供燃料，所述结合口袋足够灵活以遭受来自构象约束的熵的最小损失。
Several serotonin reuptake inhibitors are in clinical use for treatment of depression and anxiety disorders. However, to date, reported pharmacological differentiation of these ligands has focused mainly on their equilibrium binding affinities for the serotonin transporter. This study takes a new look at antidepressant binding modes using radioligand binding assays with [H-3]S-citalopram to determine equilibrium and kinetic rate constants across multiple temperatures. The observed dissociation rate constants at 26 C fall into a narrow range for all molecules. Conversely, association rate constants generally decreased with increasing equilibrium binding affinities. Consistent with this, the measured activation energy for S-citalopram association was relatively large (19.5 kcal . mol(-1)), suggesting conformational change upon ligand binding. For most of the drugs, including citalopram, the enthalpy (Delta H-O) and entropy (-T Delta S-O) contributions to reaction energetics were determined by van't Hoff analyses to be roughly equivalent (25-75% Delta G(O)) and to correlate (positively for enthalpy) with the polar surface area of the drug. However, the binding of the drug fluvoxamine was predominantly entropically driven. When these data are considered in the context of the physicochemical properties of these ligands, two distinct binding modes can be proposed. The citalopram-type binding mode probably uses a polar binding pocket that allows charged or polar interactions between ligand and receptor with comparatively small loss in enthalpy due to dehydration. The fluvoxamine-type binding mode is fueled by energy released upon burying hydrophobic ligand moieties into a binding pocket that is flexible enough to suffer minimal loss in entropy from conformational constraint.