Hasegawa Takeshi, Sugita Masatake, Kikuchi Takeshi, Hirata Fumio
Department of Bioinformatics, College of Life Science, Ritsumeikan University , 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan.
Toyota Physical and Chemical Research Institute , 41-1 Yokomichi, Nagakute, Aichi 480-1192, Japan.
J Chem Inf Model. 2017 Nov 27;57(11):2789-2798. doi: 10.1021/acs.jcim.7b00158. Epub 2017 Nov 1.
A systematic study of the binding affinities of 16 lead compounds targeting the Pim-1 kinase based on the 3D-RISM/KH theory and MD simulations is reported. The results show a correlation coefficient R = 0.69 between the theoretical and experimental values of the binding free energy. This demonstrates that the method is applicable to the problem of compound screening and lead optimization, for which relative values of the free energy among the compounds have significance. We elucidate the contribution of the ligand fragments to the binding free energy. Our results indicate that the interactions between the residues and the triazolo[4,3-b]pyridazine scaffold as well as the phenyl ring of the ligand molecule make significant contributions to stabilization of the complex. Using the 3D-RISM/KH theory, we further analyze the probability distribution of a ligand fragment around the protein-ligand complex in which the substituent around the phenyl ring is removed from the ligand. The results demonstrate that the 3D-RISM/KH theory is capable of predicting the position of substitution on a ligand that has a higher affinity to a target protein.
报道了一项基于3D-RISM/KH理论和分子动力学（MD）模拟对16种靶向Pim-1激酶的先导化合物结合亲和力的系统研究。结果表明，结合自由能的理论值与实验值之间的相关系数R = 0.69。这表明该方法适用于化合物筛选和先导优化问题，其中化合物之间自由能的相对值具有重要意义。我们阐明了配体片段对结合自由能的贡献。我们的结果表明，残基与三唑并[4,3-b]哒嗪支架以及配体分子的苯环之间的相互作用对复合物的稳定起了重要作用。利用3D-RISM/KH理论，我们进一步分析了从配体中去除苯环周围取代基的蛋白质-配体复合物周围配体片段的概率分布。结果表明，3D-RISM/KH理论能够预测对靶蛋白具有更高亲和力的配体上的取代位置。
