采用分子模拟方法探究巨噬细胞移动抑制因子与异噁唑类抑制剂的结合模式及相互作用

Molecular simulation for exploring the binding mode and interaction between Macrophage migration inhibitory factor and isoxazole inhibitors

目的采用分子模拟方法探究巨噬细胞移动抑制因子(Macrophage migration inhibitory factor, MIF)与异噁唑类抑制剂的结合模式及相互作用,设计出更强抗炎活性的MIF抑制剂。方法基于MIF与典型的异噁唑类抑制剂ISO-1及其类似物ISO-66的晶体结构1LJT、4K9G,采用Glide半柔性分子对接方法中3种不同精度的打分函数(HTVS、SP、XP),将已知的ISO-1系列抑制剂分别对接到MIF结合口袋中。通过比较对接打分与实验活性的线性相关性,获得最优的晶体结构和打分模式;接着分析MIF重要氨基酸残基与ISO-1类似物侧链基团的相互作用及结构决定性因素。在此基础上,设计了6个新颖的MIF抑制剂分子,并对它们进行分子对接打分及成药性预测。结果根据对接打分发现,4K9G-HTVS模式可以获得最佳的受体-配体结合亲和力排序,通过在R侧链引入较大的非极性基团可以与Pro33、Ile64、Trp108、Phe113等形成较强的疏水相互作用。理论预测结果显示,设计的6个新颖结构的ISO-1类似物,具有较强的MIF抑制活性和较好的成药性。结论本文计算结果为深入了解MIF与配体的结合机理,理性设计具有更强抗炎活性和成药性的ISO-1衍生物提供了理论基础。

Objective In order to design more potent anti-inflammatory Macrophage migration inhibitory factor(MIF) inhibitors, molecular simulation methods were used to explore the binding mode and interaction between MIF and isoxazole inhibitors. Methods Based on the crystal structures of MIF in complex with ISO-1 and its analogue ISO-66(1 LJT, 4 K9 G), a series of ISO-1 inhibitors are docked into the binding pocket of MIF by using semi-flexible Glide and three different precision scoring functions(HTVS, SP and XP). By comparing the linear correlation between the three different docking precision docking scores and the experimental activity, the optimal crystal structure and scoring mode were obtained. Then, the interaction between the important residues of MIF and the side chain groups of ISO-1 analogs and the structural determinants were analyzed. On this basis, several novel MIF inhibitors were designed, followed by molecular docking scoring and druggability prediction. Results According to the docking score, it is found that the 4 K9 G-HTVS mode could obtain the best result to rank receptor-ligand binding affinity. By introducing a larger non-polar group in the R side chain, it could form a stronger hydrophobic interaction with Pro33, Ile64, Trp108 and Phe113. Theoretical predictions confirmed that the six designed ISO-1 analogues had good inhibitory activity and acceptable druggability. Conclusion These calculation results provide a solid theoretical basis for in-depth understanding of the binding mechanisms of MIF and ligands, and rational design of ISO-1 derivatives with more potent activity and druggability.