目的 研究吲哚类双靶点Src/IGF-1R抑制剂与两个受体的作用机制.方法 用分子对接和分子动力学(MD)模拟方法确定化合物与两个激酶的结合模式和相互作用的关键氨基酸,并用MM-PBSA法计算化合物与受体的结合自由能.结果 通过对接发现抑制剂在两个激酶中的结合模式非常相似,化合物的对接能量打分与它们的抑制活性具有良好的相关性(Src的R=0.800;IGF-1R的R=0.891),两个激酶蛋白结构叠合的均方根偏差和标准分数分别为0.18 nm和7.02 nm,蛋白序列36.00％是相同的,表明Src与IGF-1R两蛋白链相似度较高.分子动力学模拟进一步验证对接结果的稳定性和合理性,化合物的结合自由能与实验活性有很好的相关性.MM-GBSA能量分解表明,疏水相互作用是化合物与Src和IGF-1R结合的主要驱动力.配体与Ser345和Asp404残基之间的氢键相互作用有助于稳定配体在Src结合袋的构象.结论 吲哚类衍生物与Src和IGF-1R的结合位点信息可很好地阐释化合物的作用机制,为新型Src/IGF-1R双靶点抑制剂的设计提供实验依据.
Objective To study the action mechanism of indoles furnished dual c-Src/IGF-1 R inhibitors with two receptors. Methods The binding modes of these compounds interacting with both c-Src and IGF-1 R kinases and the key amino acid residues at the binding pockets were revealed by molecular docking and molecular dynamics (MD) simulation. The binding free energy of these compounds to Src and IGF-1 R kinases was calculated by MM-PBSA method. Results The binding patterns of the inhibitors in two kinases were found to be very similar by docking, and the docking scores of these compounds were closely related to their experimental activities. The correlation coefficients of Src and IGF-1 R were R=0.800 and R=0.891, respectively. The RMSD and Z score of the two kinases protein superposition were 0.18 nm and 7.02 nm, respectively, and the protein sequence was 36.00％ identical, indicating that the Src and IGF-1 R protein chains were highly similar. Molecular dynamics further demonstrated the stability and rationality of docking results. The binding free energies of compounds had a good correlation with the experimental activities. MM-GBSA energy decomposition indicated that the hydrophobic interaction was the major driving force for the binding of compounds to Src and IGF-1 R. The hydrogen bond interactions between the ligands and residues Ser345 and Asp404 helped to stabilize the conformation of ligands at the Src binding pocket. Conclusion The results can provide information for better understanding of the action mechanism of these indole inhibitos and thus be helpful in design novel potent dual Src/IGF-1 R inhibitors.
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