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首页> 美国卫生研究院文献>Computational and Structural Biotechnology Journal >Towards good correlation between fragment molecular orbital interaction energies and experimental IC50 for ligand binding: A case study of p38 MAP kinase
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Towards good correlation between fragment molecular orbital interaction energies and experimental IC50 for ligand binding: A case study of p38 MAP kinase

机译：碎片分子轨道相互作用能与配体结合实验IC50之间的良好相关性：以p38 MAP激酶为例

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We describe several procedures for the preprocessing of fragment molecular orbital (FMO) calculations on p38 mitogen-activated protein (MAP) kinase and discuss the influence of the procedures on the protein–ligand interaction energies represented by inter-fragment interaction energies (IFIEs). The correlation between the summation of IFIEs for a ligand and amino acid residues of protein (IFIE-sum) and experimental affinity values (IC50) was poor when considered for the whole set of protein–ligand complexes. To improve the correlation for prediction of ligand binding affinity, we carefully classified data set by the ligand charge, the DFG-loop state (DFG-in/out loop), which is characteristic of kinase, and the scaffold of ligand. The correlation between IFIE-sums and the activity values was examined using the classified data set. As a result, it was confirmed that there was a selected data set that showed good correlation between IFIE-sum and activity value by appropriate classification. In addition, we found that the differences in protonation and hydrogen orientation caused by subtle differences in preprocessing led to a relatively large difference in IFIE values. Further, we also examined the effect of structure optimization with different force fields. It was confirmed that the difference in the force field had no significant effect on IFIE-sum. From the viewpoint of drug design using FMO calculations, various investigations on IFIE-sum in this research, such as those regarding several classifications of data set and the different procedures of structural preparation, would be expected to provide useful knowledge for improvement of prediction ability about the ligand binding affinity.
机译：我们描述了对p38丝裂原活化蛋白（MAP）激酶进行片段分子轨道（FMO）预处理的几种程序，并讨论了该程序对以片段间相互作用能（IFIEs）表示的蛋白-配体相互作用能的影响。当考虑整套蛋白质-配体复合物时，配体的IFIE和蛋白质的氨基酸残基之和（IFIE-sum）与实验亲和力值（IC50）之间的相关性很差。为了改善预测配体结合亲和力的相关性，我们通过配体电荷，激酶的特征性DFG环状态（DFG入/出环）和配体支架对数据集进行了仔细分类。使用分类数据集检查IFIE和与活动值之间的相关性。结果，证实了通过适当的分类，存在选择的数据集，其显示出IFIE-sum和活性值之间的良好相关性。此外，我们发现，由于预处理中的细微差异而导致的质子化和氢取向差异导致IFIE值相对较大。此外，我们还研究了在不同力场下结构优化的效果。可以确定，力场的差异对IFIE-sum的影响不大。从使用FMO计算的药物设计的角度来看，本研究中有关IFIE-sum的各种研究，如有关数据集的几种分类以及结构制备的不同程序的研究，有望为提高有关FIE的预测能力提供有用的知识。配体结合亲和力。

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