Investigation on the binding mechanism of loratinib with the c-ros oncogene 1 (ROS1) receptor tyrosine kinase via molecular dynamics simulation and binding free energy calculations
Investigation on the binding mechanism of loratinib with the c-ros oncogene 1 (ROS1) receptor tyrosine kinase via molecular dynamics simulation and binding free energy calculations
复制标题
通过分子动力学模拟和结合自由能计算研究劳拉替尼与c-ros癌基因1（ROS1）受体酪氨酸激酶的结合机制
DOI：
10.1080/07391102.2017.1378127
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Jiajie Zhang
中科院分区：
文献类型：
--
作者：
Xiaoyun Wu;Yuanyuan Wang;Shanhe Wan;Jiajie Zhang
c-ros致癌基因1 （ROS1）已被证明是治疗各种人类癌症的重要癌症靶点。间变性淋巴瘤激酶抑制剂克唑替尼已于2016年获得美国食品和药物管理局批准用于治疗ROS1阳性转移性非小细胞肺癌患者。然而，在临床研究中，由于甘氨酸2032对精氨酸（G2032R）的继发性突变，出现了严重的耐药性。克唑替尼的大环类似物Loratinib （PF-06463922）对野生型（WT） ROS1和ROS1G2032R突变体的抑制活性显著提高。为了深入了解其抑制机制，我们对loratinib与WT和G2032R突变的ROS1的配合物进行了分子动力学模拟和自由能计算。载脂蛋白ros1wt和载脂蛋白ROS1G2032R的RMSF分布相似，ROS1G2032R-loratinib的RMSF分布明显高于WT的ROS1-loratinib，这表明loratinib与ROS1G2032R的结合显著干扰了蛋白的波动。结合自由能的计算表明，G2032R突变显著降低了loratinib对ROS1的结合亲和力，这主要是由于构象熵的增加和溶剂化能的降低。此外，详细的每残基结合自由能突出了G2032R突变体系中某些残基的贡献增加或减少。本研究揭示了loratinib作为强效WT和G2032R突变ROS1抑制剂的详细抑制机制，有望为合理的药物设计提供依据。
The c-ros oncogene 1 (ROS1) has proven to be an important cancer target for the treatment of various human cancers. The anaplastic lymphoma kinase inhibitor crizotinib has been granted approval for the treatment of patients with ROS1 positive metastatic non-small-cell lung cancer by the Food and Drug Administration on 2016. However, serious resistance due to the secondary mutation of glycine 2032 to arginine (G2032R) was developed in clinical studies. Loratinib (PF-06463922), a macrocyclic analog of crizotinib, showed significantly improved inhibitory activity against wild–type (WT) ROS1 and ROS1G2032R mutant. To provide insights into the inhibition mechanism, molecular dynamics simulations and free energy calculations were carried out for the complexes of loratinib with WT and G2032R mutated ROS1. The apo-ROS1WT and apo-ROS1G2032R systems showed similar RMSF distributions, while ROS1G2032R-loratinib showed significantly higher than that of WT ROS1-loratinib, which revealed that the binding of loratinib to ROS1G2032R significantly interfered the fluctuation of protein. Calculations of binding free energies indicate that G2032R mutation significantly reduces the binding affinity of loratinib for ROS1, which arose mostly from the increase of conformation entropy and the decrease of solvation energy. Furthermore, detailed per-residue binding free energies highlighted the increased and decreased contributions of some residues in the G2032R mutated systems. The present study revealed the detailed inhibitory mechanism of loratinib as potent WT and G2032R mutated ROS1 inhibitor, which was expected to provide a basis for rational drug design.
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影响因子：
5.5
作者：
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通讯作者：
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作者：
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作者：
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通讯作者：
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