Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, Jilin University, Changchun, People's Republic of China.
Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun, People's Republic of China.
J Cell Biochem. 2018 Jul;119(7):5332-5342. doi: 10.1002/jcb.26666. Epub 2018 Apr 6.
Alectinib, a highly selective next-genetation anaplastic lymphoma kinase (ALK) inhibitor, has demonstrated promising antitumor activity in patients with ALK-positive non-small cell lung carcinomas (NSCLC). However, the therapeutic benefits of alectinib is inescapably hampered by the development of acquired resistant mutations in ALK. Despite the availability of ample experimental mutagenesis data, the molecular origin and the structural motifs under alectinib binding affinity deficiencies are still ambiguous. Here, molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GBSA) calculation approaches were employed to elucidate the mechanisms of alectinib resistance induced by the mutations I1171N, V1180L, and L1198F. The MD results reveal that the studied mutations could trigger the dislocation of alectinib as well as conformational changes at the inhibitor binding site, thus induce the interactional changes between alectinib and mutants. The most influenced regions are the ligand binding entrance and the hinge region, which are considered to be the dominant binding motifs accounting for the binding affinity loss in mutants. The "key and lock mechanism" between the ethyl group at position 9 of alectinib and a recognition cavity in the hinge region of ALK is presented to illustrate the major molecular origin of drug resistance. Our results provide mechanistic insight into the effect of ALK mutations resistant to alectinib, which could contribute to further rational design of inhibitors to combat the acquired resistance.
艾乐替尼是一种高度选择性的下一代间变性淋巴瘤激酶（ALK）抑制剂，在ALK 阳性非小细胞肺癌（NSCLC）患者中显示出有希望的抗肿瘤活性。然而，艾乐替尼的治疗益处不可避免地受到 ALK 获得性耐药突变的阻碍。尽管有大量的实验诱变数据，但艾乐替尼结合亲和力不足的分子起源和结构基序仍不清楚。在这里，采用分子动力学（MD）模拟和分子力学广义 Born 表面积（MM-GBSA）计算方法来阐明突变 I1171N、V1180L 和 L1198F 引起的艾乐替尼耐药的机制。MD 结果表明，研究的突变可引发艾乐替尼的脱位以及抑制剂结合位点的构象变化，从而导致艾乐替尼与突变体之间的相互作用变化。受影响最大的区域是配体结合入口和铰链区域，这被认为是主要的结合基序，导致突变体结合亲和力丧失。提出了艾乐替尼 9 位的乙基基团与 ALK 铰链区域的识别腔之间的“钥匙和锁机制”，以说明耐药的主要分子起源。我们的结果深入了解了艾乐替尼耐药的 ALK 突变的影响，这有助于进一步合理设计抑制剂来对抗获得性耐药。
