Kay Maryam, Dehghanian Fariba
Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Islamic Republic of Iran.
Division of Genetics, Department of Biology, Faculty of Science, University of Isfahan, Isfahan, Islamic Republic of Iran.
J Mol Model. 2017 Oct 24;23(11):323. doi: 10.1007/s00894-017-3495-5.
Crizotinib is an anticancer tyrosine kinase inhibitor that is approved for use as a first-line treatment for some non-small-cell lung cancers. L1196M is the most frequently observed mutation in NSCLC patients. This mutation, known as the gatekeeper mutation in the ALK kinase domain, confers resistance to crizotinib by sterically blocking the binding of the drug. However, the molecular mechanism of crizotinib resistance caused by the L1196M mutation is still unclear. Molecular dynamics simulation was therefore utilized in this study to investigate the mechanism by which the L1196M mutation may affect crizotinib resistance. Our results suggest that larger fluctuations in some important regions of the mutant complex compared to the wild-type complex may contribute to the resistance of the mutant complex to crizotinib. Also, mutation-induced alterations to the secondary structure of the complex as well as unstable hydrogen-bonding patterns in the A-loop and P-loop regions decrease the total binding energy of the complex. This study therefore provides a molecular explanation for the resistance to crizotinib caused by the L1196M mutation, which could aid the design of more efficient and selective drugs.
克唑替尼是一种抗癌酪氨酸激酶抑制剂，被批准用作某些非小细胞肺癌的一线治疗药物。L1196M是在非小细胞肺癌患者中最常观察到的突变。这种突变在ALK激酶结构域中被称为守门人突变，通过空间位阻阻断药物结合而赋予对克唑替尼的抗性。然而，由L1196M突变引起的克唑替尼抗性的分子机制仍不清楚。因此，本研究利用分子动力学模拟来研究L1196M突变可能影响克唑替尼抗性的机制。我们的结果表明，与野生型复合物相比，突变体复合物某些重要区域的较大波动可能导致突变体复合物对克唑替尼产生抗性。此外，突变引起的复合物二级结构改变以及A环和P环区域不稳定的氢键模式降低了复合物的总结合能。因此，本研究为L1196M突变导致的克唑替尼抗性提供了分子解释，这有助于设计更高效、更具选择性的药物。
