Insight into drug resistance mechanisms and discovery of potential inhibitors against wild-type and L1196M mutant ALK from FDA-approved drugs
Insight into drug resistance mechanisms and discovery of potential inhibitors against wild-type and L1196M mutant ALK from FDA-approved drugs
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DOI：
10.1007/s00894-016-3099-5
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发表时间：
2016-09-01
影响因子：
2.2
通讯作者：
Bao, Jinku
中科院分区：
文献类型：
--
作者：
Li, Jianzong;Liu, Wei;Bao, Jinku
间变性淋巴瘤激酶（ALK）在多种恶性肿瘤中起着至关重要的作用。它被认为是治疗ALK依赖性癌症的公认靶点。尽管已经做出了大量努力来开发ALK抑制剂，但只有克唑替尼，ceritinib和alectinib已被美国食品和药物管理局批准用于ALK阳性非小细胞肺癌（NSCLC）患者。ALK阳性肿瘤的继发性耐药突变给开发有效药物带来困难。为了全面了解抑制剂对ALK酪氨酸激酶突变反应的分子机制，我们通过计算方法建立了对药物抗ALK突变的广泛特征的准确评估。采用基于分子动力学（MD）模拟的分子力学-广义玻恩表面积（MM-GBSA）方法计算了受体-药物体系的相对结合自由能。此外，还利用基于结构的虚拟筛选从3180种已批准的药物中筛选出针对野生型ALK和看门突变L1196 M的有效抑制剂。最后，对ALK的耐药机制进行了探讨，并成功鉴定了几种新的野生型和L1196 M突变型ALK抑制剂。
Anaplastic lymphoma kinase (ALK) plays a crucial role in multiple malignant cancers. It is known as a well-established target for the treatment of ALK-dependent cancers. Even though substantial efforts have been made to develop ALK inhibitors, only crizotinib, ceritinib, and alectinib had been approved by the U.S. Food and Drug Administration for patients with ALK-positive non-small cell lung cancer (NSCLC). The secondary mutations with drug-resistance bring up difficulties to develop effective drugs for ALK-positive cancers. To give a comprehensive understanding of molecular mechanism underlying inhibitor response to ALK tyrosine kinase mutations, we established an accurate assessment for the extensive profile of drug against ALK mutations by means of computational approaches. The molecular mechanics-generalized Born surface area (MM-GBSA) method based on molecular dynamics (MD) simulation was carried out to calculate relative binding free energies for receptor-drug systems. In addition, the structure-based virtual screening was utilized to screen effective inhibitors targeting wild-type ALK and the gatekeeper mutation L1196M from 3180 approved drugs. Finally, the mechanism of drug resistance was discussed, several novel potential wild-type and L1196M mutant ALK inhibitors were successfully identified.