Quantum mechanical pairwise decomposition analysis of protein kinase B inhibitors: validating a new tool for guiding drug design.
Quantum mechanical pairwise decomposition analysis of protein kinase B inhibitors: validating a new tool for guiding drug design.
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蛋白激酶 B 抑制剂的量子机械成对分解分析：验证指导药物设计的新工具。
DOI：
10.1021/ci9003333
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发表时间：
2010
影响因子：
5.6
通讯作者：
Westerhoff,LanceM
中科院分区：
文献类型：
--
作者：
Zhang,Xiaohua;Gibbs,AlanC;Reynolds,CharlesH;Peters,MartinB;Westerhoff,LanceM
对基于片段和结构的药物设计衍生的一系列蛋白激酶B(PKB)抑制剂进行了量子力学半经验比较结合能计算。之所以选择这些蛋白质−配体复合体，是因为它们代表了一组一致的实验数据，包括晶体结构和亲和力。基于PM3和AM1哈密顿量对7个评分函数进行了评估。通过对对准姿势的偏最小二乘分析获得的最优模型是预测性的，如通过许多标准统计标准和外部数据集的验证来衡量的。已经开发出一种算法，该算法为总体结合亲和力提供基于残基的贡献。这些基于残基的结合贡献可以在热图中绘制，以便突出配体结合最重要的残基。在这些PKB抑制剂的情况下，MAP显示Met166、Thr97、Gly43、Glu114、Ala116和Val50等残基在确定结合亲和力方面发挥重要作用。相互作用能图使得识别对配体结合有最大绝对影响的残基变得容易。结构与活性关系图(Structure−Activity Relationship，SAR图)突出了对区分强效配体最关键的残基。总而言之，相互作用能量和合成孔径雷达图谱为药物设计提供了有用的见解，这是任何其他方式都难以获得的。
Quantum mechanical semiempirical comparative binding energy analysis calculations have been carried out for a series of protein kinase B (PKB) inhibitors derived from fragment- and structure-based drug design. These protein−ligand complexes were selected because they represent a consistent set of experimental data that includes both crystal structures and affinities. Seven scoring functions were evaluated based on both the PM3 and the AM1 Hamiltonians. The optimal models obtained by partial least-squares analysis of the aligned poses are predictive as measured by a number of standard statistical criteria and by validation with an external data set. An algorithm has been developed that provides residue-based contributions to the overall binding affinity. These residue-based binding contributions can be plotted in heat maps so as to highlight the most important residues for ligand binding. In the case of these PKB inhibitors, the maps show that Met166, Thr97, Gly43, Glu114, Ala116, and Val50, among other residues, play an important role in determining binding affinity. The interaction energy map makes it easy to identify the residues that have the largest absolute effect on ligand binding. The structure−activity relationship (SAR) map highlights residues that are most critical to discriminating between more and less potent ligands. Taken together the interaction energy and the SAR maps provide useful insights into drug design that would be difficult to garner in any other way.