Non-additivity of Functional Group Contributions in Protein Ligand Binding: A Comprehensive Study by Crystallography and Isothermal Titration Calorimetry
Non-additivity of Functional Group Contributions in Protein Ligand Binding: A Comprehensive Study by Crystallography and Isothermal Titration Calorimetry
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DOI：
10.1016/j.jmb.2010.02.007
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发表时间：
2010-04-09
影响因子：
5.6
通讯作者：
Klebe, Gerhard
中科院分区：
文献类型：
--
作者：
Baum, Bernhard;Muley, Laveena;Klebe, Gerhard
在药物化学中，官能团对蛋白质配体结合的贡献是一个非常流行的概念，它是合理设计和优化先导结构的基础。目前应用的对接评分函数大多建立在这种加性模型的基础上。尽管这一概念的局限性是众所周知的，但详细研究为什么分子水平上的可加性失败的案例研究仍然非常少。通过对一系列同类凝血酶抑制剂的晶体结构分析和等温滴定量热法研究表明，通过形成的络合物的动力学性质，疏水接触和氢键形成之间的广泛协同作用是紧密耦合的。与凝血酶S3口袋表面形成最佳亲脂接触并完全去溶解该口袋可能与在配体和蛋白质之间形成最佳氢键相冲突。竞争相互作用的相互作用依赖于配体疏水取代基的大小，并影响配体部分在结合部位的剩余迁移率。对单个晶体结构的分析以及将自由能分解为焓和熵的结果表明，配体的结合亲和力是氢键和疏水接触的焓贡献以及结合配体的剩余迁移率损失增加的熵考虑的结果。这种相互竞争和部分补偿的热效应和熵效应的复杂图景决定了自由能对分子水平上的配体结合的贡献的非加性。(C)2010爱思唯尔有限公司。保留所有权利。
Additivity of functional group contributions to protein ligand binding is a very popular concept in medicinal chemistry as the basis of rational design and optimized lead structures. Most of the currently applied scoring functions for docking build on such additivity models. Even though the limitation of this concept is well known, case studies examining in detail why additivity fails at the molecular level are still very scarce. The present study shows, by use of crystal structure analysis and isothermal titration calorimetry for a congeneric series of thrombin inhibitors, that extensive cooperative effects between hydrophobic contacts and hydrogen bond formation are intimately coupled via dynamic properties of the formed complexes. The formation of optimal lipophilic contacts with the surface of the thrombin S3 pocket and the full desolvation of this pocket can conflict with the formation of an optimal hydrogen bond between ligand and protein. The mutual contributions of the competing interactions depend on the size of the ligand hydrophobic substituent and influence the residual mobility of ligand portions at the binding site. Analysis of the individual crystal structures and factorizing the free energy into enthalpy and entropy demonstrates that binding affinity of the ligands results from a mixture of enthalpic contributions from hydrogen bonding and hydrophobic contacts, and entropic considerations involving an increasing loss of residual mobility of the bound ligands. This complex picture of mutually competing and partially compensating enthalpic and entropic effects determines the non-additivity of free energy contributions to ligand binding at the molecular level. (C) 2010 Elsevier Ltd. All rights reserved.