Compensating enthalpic and entropic changes hinder binding affinity optimization
Compensating enthalpic and entropic changes hinder binding affinity optimization
复制标题
DOI：
10.1111/j.1747-0285.2007.00519.x
复制
发表时间：
2007-06-01
影响因子：
3
通讯作者：
Freire, Ernesto
中科院分区：
文献类型：
--
作者：
Lafont, Virginie;Armstrong, Anthony A.;Freire, Ernesto
提高候选药物效力的常见策略是在能够与靶标建立强相互作用的位置引入化学功能，例如氢键供体或受体。然而，经常观察到添加的官能团即使形成强氢键，也不一定会提高效力。在这里，我们探索这些观察的热力学和结构基础。 KNI-10033 是一种有效的实验性 HIV-1 蛋白酶抑制剂，对野生型酶具有皮摩尔亲和力 (K-d = 13 pm)。抑制剂的效力是有利的焓 (Delta H = -8.2 kcal/mol) 和熵 (-T Delta S = -6.7 kcal/mol) 相互作用的结果。 KNI-10033 中的硫醚基团被磺酰基 (KNI-10075) 取代，从而与 HIV-1 蛋白酶的 Asp 30B 的酰胺形成强氢键。这个额外的氢键将结合焓提高了 3.9 kcal/mol；然而，熵增益完全由熵损失补偿，不会导致亲和力变化。抑制剂/蛋白酶复合物的晶体学和热力学分析表明，熵损失是由于构象效应和溶剂化效应的结合造成的。这些结果提供了一套旨在克服熵/熵补偿并提高结合效力的实用指南。
A common strategy to improve the potency of drug candidates is to introduce chemical functionalities, like hydrogen bond donors or acceptors, at positions where they are able to establish strong interactions with the target. However, it is often observed that the added functionalities do not necessarily improve potency even if they form strong hydrogen bonds. Here, we explore the thermodynamic and structural basis for those observations. KNI-10033 is a potent experimental HIV-1 protease inhibitor with picomolar affinity against the wild-type enzyme (K-d = 13 pm). The potency of the inhibitor is the result of favorable enthalpic (Delta H = -8.2 kcal/mol) and entropic (-T Delta S = -6.7 kcal/mol) interactions. The replacement of the thioether group in KNI-10033 by a sulfonyl group (KNI-10075) results in a strong hydrogen bond with the amide of Asp 30B of the HIV-1 protease. This additional hydrogen bond improves the binding enthalpy by 3.9 kcal/mol; however, the enthalpy gain is completely compensated by an entropy loss, resulting in no affinity change. Crystallographic and thermodynamic analysis of the inhibitor/protease complexes indicates that the entropy losses are due to a combination of conformational and solvation effects. These results provide a set of practical guidelines aimed at overcoming enthalpy/entropy compensation and improve binding potency.