Analyzing resistance pattern of non-small cell lung cancer to crizotinib using molecular dynamic approaches.

IF 1.5 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Indian journal of biochemistry & biophysics Pub Date : 2015-02-01

Anish Kumar, K Ramanathan

引用次数: 0

Abstract

Crizotinib is the potential anticancer drug used for the treatment of non-small cell lung cancer (NSCLC) approved by FDA in 2011. The main target for the crizotinib is anaplastic lymphoma kinase (ALK). Evidences available indicate that double mutant ALK (L1196M and G1269A) confers resistance to crizotinib. However, how mutation confers drug resistance is not well-understood. Hence, in the present study, molecular dynamic (MD) simulation approach was employed to study the impact of crizotinib binding efficacy with ALK structures at a molecular level. Docking results indicated that ALK double mutant (L1196M and G1269A) significantly affected the binding affinity for crizotinib. Furthermore, MD studies revealed that mutant ALK-crizotinib complex showed higher deviation, higher fluctuation and decreased number of intermolecular H-bonds, when compared to the native ALK-crizotinib complex. These results may be immense importance for the molecular level understanding of the crizotinib resistance pattern and also for designing potential drug molecule for the treatment of lung cancer.

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应用分子动力学方法分析非小细胞肺癌对克唑替尼的耐药模式。

克唑替尼是FDA于2011年批准用于治疗非小细胞肺癌(NSCLC)的潜在抗癌药物。克唑替尼的主要靶点是间变性淋巴瘤激酶(ALK)。现有证据表明，双突变ALK (L1196M和G1269A)对克唑替尼具有耐药性。然而，突变是如何产生耐药性的还不清楚。因此，本研究采用分子动力学(MD)模拟方法，在分子水平上研究克唑替尼与ALK结构结合效能的影响。对接结果表明，ALK双突变体(L1196M和G1269A)显著影响了其对克唑替尼的结合亲和力。此外，MD研究表明，与天然alk -克里唑替尼复合物相比，突变体alk -克里唑替尼复合物表现出更高的偏差、更高的波动和更少的分子间氢键数量。这些结果对于在分子水平上了解克唑替尼耐药模式以及设计治疗肺癌的潜在药物分子具有重要意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Indian journal of biochemistry & biophysics 生物-生化与分子生物学

CiteScore

2.90

自引率

50.00%

发文量

审稿时长

3 months

期刊介绍： Started in 1964, this journal publishes original research articles in the following areas: structure-function relationships of biomolecules; biomolecular recognition, protein-protein and protein-DNA interactions; gene-cloning, genetic engineering, genome analysis, gene targeting, gene expression, vectors, gene therapy; drug targeting, drug design; molecular basis of genetic diseases; conformational studies, computer simulation, novel DNA structures and their biological implications, protein folding; enzymes structure, catalytic mechanisms, regulation; membrane biochemistry, transport, ion channels, signal transduction, cell-cell communication, glycobiology; receptors, antigen-antibody binding, neurochemistry, ageing, apoptosis, cell cycle control; hormones, growth factors; oncogenes, host-virus interactions, viral assembly and structure; intermediary metabolism, molecular basis of disease processes, vitamins, coenzymes, carrier proteins, toxicology; plant and microbial biochemistry; surface forces, micelles and microemulsions, colloids, electrical phenomena, etc. in biological systems. Solicited peer reviewed articles on contemporary Themes and Methods in Biochemistry and Biophysics form an important feature of IJBB. Review articles on a current topic in the above fields are also considered. They must dwell more on research work done during the last couple of years in the field and authors should integrate their own work with that of others with acumen and authenticity, mere compilation of references by a third party is discouraged. While IJBB strongly promotes innovative novel research works for publication as full length papers, it also considers research data emanating from limited objectives, and extension of ongoing experimental works as ‘Notes’. IJBB follows “Double Blind Review process” where author names, affiliations and other correspondence details are removed to ensure fare evaluation. At the same time, reviewer names are not disclosed to authors.