Hunan Province Key Laboratory of Materials Surface & Interface Science and Technology, College of Science, Central South University of Forestry and Technology, Changsha, Hunan, China.
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Chem Biol Drug Des. 2019 May;93(5):934-948. doi: 10.1111/cbdd.13493. Epub 2019 Feb 19.
Lenvatinib (LEN), sorafenib (SOR), and sunitinib (SUN) are drugs targeting vascular endothelial growth factor receptor 2 (VEGFR2). Despite sharing similar chemical structures and bioactivities, LEN and SOR bind to different functional states of VEGFR2, viz. DFG-in and DFG-out state, respectively. SUN binds to the DFG-out state of VEGFR2 just like SOR but with less potency. Thus, detail binding mechanisms between VEGFR2 and these drugs, especially dynamic interaction, are valuable for future drug design. In the present work, molecular dynamics simulation, essential dynamic analysis, and molecular mechanics/generalized born surface area were performed to these VEGFR2-drugs systems. Rank of calculated binding affinities is in accordance with the experimental data. The binding free energy calculation suggests that van der Waals interaction plays a vital role in the binding. Per-residue free energy decomposition indicates that residues L840, V848, A866, E885, L889, V899, V916, F918, C919, L1035, C1045, D1046, and F1047 play an important role in the binding between VEGFR2 and LEN/SOR. While residues L840, V848, E917, F918, C919, G922, L1035, and F1047 contribute the major hydrophobic interaction for SUN binding to the receptor. Our results also reveal that residue E885/D1046 plays a vital role in binding via forming hydrogen bonds with drugs.
仑伐替尼（LEN）、索拉非尼（SOR）和舒尼替尼（SUN）是靶向血管内皮生长因子受体 2（VEGFR2）的药物。尽管它们具有相似的化学结构和生物活性，但 LEN 和 SOR 分别结合 VEGFR2 的不同功能状态，即 DFG-in 和 DFG-out 状态。SUN 像 SOR 一样结合 VEGFR2 的 DFG-out 状态，但亲和力较弱。因此，这些药物与 VEGFR2 的详细结合机制，特别是动态相互作用，对于未来的药物设计非常有价值。在本工作中，我们对 VEGFR2-药物系统进行了分子动力学模拟、本质动力学分析和分子力学/广义 Born 表面积分析。计算结合亲和力的顺序与实验数据一致。结合自由能计算表明范德华相互作用在结合中起着至关重要的作用。残基自由能分解表明，残基 L840、V848、A866、E885、L889、V899、V916、F918、C919、L1035、C1045、D1046 和 F1047 在 VEGFR2 与 LEN/SOR 结合中起重要作用。而残基 L840、V848、E917、F918、C919、G922、L1035 和 F1047 对 SUN 与受体的结合贡献主要的疏水性相互作用。我们的结果还表明，残基 E885/D1046 通过与药物形成氢键在结合中起着至关重要的作用。
