Xie Huiding, Li Yupeng, Yu Fang, Xie Xiaoguang, Qiu Kaixiong, Fu Jijun
Department of Chemistry, Yunnan University, Kunming 650091, China.
Department of Chemistry, School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China.
Int J Mol Sci. 2015 Nov 16;16(11):27350-61. doi: 10.3390/ijms161126026.
In the recent cancer treatment, B-Raf kinase is one of key targets. Nowadays, a group of imidazopyridines as B-Raf kinase inhibitors have been reported. In order to investigate the interaction between this group of inhibitors and B-Raf kinase, molecular docking, molecular dynamic (MD) simulation and binding free energy (ΔGbind) calculation were performed in this work. Molecular docking was carried out to identify the key residues in the binding site, and MD simulations were performed to determine the detail binding mode. The results obtained from MD simulation reveal that the binding site is stable during the MD simulations, and some hydrogen bonds (H-bonds) in MD simulations are different from H-bonds in the docking mode. Based on the obtained MD trajectories, ΔGbind was computed by using Molecular Mechanics Generalized Born Surface Area (MM-GBSA), and the obtained energies are consistent with the activities. An energetic analysis reveals that both electrostatic and van der Waals contributions are important to ΔGbind, and the unfavorable polar solvation contribution results in the instability of the inhibitor with the lowest activity. These results are expected to understand the binding between B-Raf and imidazopyridines and provide some useful information to design potential B-Raf inhibitors.
在近期的癌症治疗中，B-Raf激酶是关键靶点之一。如今，已有一组作为B-Raf激酶抑制剂的咪唑并吡啶被报道。为了研究这组抑制剂与B-Raf激酶之间的相互作用，本研究进行了分子对接、分子动力学（MD）模拟以及结合自由能（ΔGbind）计算。通过分子对接确定结合位点中的关键残基，并通过MD模拟确定详细的结合模式。MD模拟结果表明，在MD模拟过程中结合位点是稳定的，且MD模拟中的一些氢键（H键）与对接模式中的氢键不同。基于所获得的MD轨迹，使用分子力学广义玻恩表面积（MM-GBSA）计算ΔGbind，所得能量与活性一致。能量分析表明，静电作用和范德华力对ΔGbind都很重要，而不利的极性溶剂化作用导致活性最低的抑制剂不稳定。这些结果有望有助于理解B-Raf与咪唑并吡啶之间的结合，并为设计潜在的B-Raf抑制剂提供一些有用信息。
