Dehghanian Fariba, Kay Maryam, Vallian Sadeq
Division of Genetics, Department of Biology, Faculty of Science, University of Isfahan, Isfahan, Islamic Republic of Iran.
Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Islamic Republic of Iran.
J Mol Graph Model. 2017 Aug;75:287-293. doi: 10.1016/j.jmgm.2017.06.010. Epub 2017 Jun 8.
Crizotinib is an efficient antineoplastic drug for treatment of non-small cell lung carcinoma (NSCLC), which is identified as an anaplastic lymphoma kinase (ALK) inhibitor. F1174V is a recently identified acquired point mutation relating to the Crizotinib resistance in NSCLC patients. The mechanism of Crizotinib resistance relating to F1174V mutation as a non-active site mutation remains unclear. In this study, the molecular dynamic simulation was used to investigate the possible mechanisms by which F1174V mutation may affect the structure and activity of ALK kinase domain. The results suggested that F1174V mutation could cause two important secondary structure alterations, which led to the local conformational change in ALK kinase domain. This causes more positive free energy in the mutant complex in comparison with the wild-type one. In addition, our structural analyses illustrated that F1174V mutation could result in some important interactions, which represent the key characteristics of the ALK active conformation. This study provided a molecular mechanism for ALK Crizotinib resistance caused by F1174V mutation,which could facilitate designing more efficient drugs.
克唑替尼是一种用于治疗非小细胞肺癌（NSCLC）的有效抗肿瘤药物，它被鉴定为一种间变性淋巴瘤激酶（ALK）抑制剂。F1174V是最近在NSCLC患者中发现的与克唑替尼耐药相关的获得性点突变。作为一种非活性位点突变，与F1174V突变相关的克唑替尼耐药机制尚不清楚。在本研究中，使用分子动力学模拟来研究F1174V突变可能影响ALK激酶结构域结构和活性的潜在机制。结果表明，F1174V突变可导致两个重要的二级结构改变，从而导致ALK激酶结构域的局部构象变化。与野生型相比，这使得突变体复合物中的自由能更正。此外，我们的结构分析表明，F1174V突变可导致一些重要的相互作用，这些相互作用代表了ALK活性构象的关键特征。本研究为F1174V突变导致的ALK克唑替尼耐药提供了分子机制，这有助于设计更有效的药物。
