Mutation L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling

doi:10.1039/c7cp05418a

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	Mutation L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling
	Chen, Jianzhong 1; Wang, Jinan 2; Zhu, Weiliang2
刊名	PHYSICAL CHEMISTRY CHEMICAL PHYSICS
	2017-11-28
卷号	19 期号:44 页码:30239-30248
ISSN号	1463-9076
DOI	10.1039/c7cp05418a
文献子类	Article
英文摘要	Anaplastic lymphoma kinase (ALK) has been regarded as a promising drug target in the treatment of tumors and the mutation L1196M induces different levels of drug resistance toward the existing inhibitors. Free energy perturbation (FEP) coupled with umbrella sampling simulation is used to investigate the conformational change of ALK induced by L1196M and drug-resistant mechanisms of L1196M on four inhibitors VGH, 3U9, 5P8 and IV7. Dynamics analysis shows that L119M produces significant influences on the flexibility of the loops L1 and L2 in ALK. FEP calculations suggest that the drug-resistant intensity of L1196M toward inhibitors decreases in the order 3U9 4 VGH 4 5P8 4 IV7, in accordance with the experimentally determined results. Moreover, statistical analysis of hydrophobic contacts of inhibitors with separate residues in ALK further demonstrates that the decrease in the hydrophobic interactions of inhibitors with L1256 mostly drives drug resistance of L1196M toward inhibitors. The calculations of potential of mean force (PMF) based on umbrella sampling simulations indicate that the free energies of inhibitor-L1196M ALKs are lower than those of inhibitor-wild ALKs. This study is expected to provide significant theoretical support which would help in the design of potent inhibitors alleviating the drug resistance of L1196M in ALK.
资助项目	National Natural Science Foundation of China[11274206] ; National Natural Science Foundation of China[81273435] ; National Natural Science Foundation of China[11504206] ; National Natural Science Foundation of China[81573350] ; National Natural Science Foundation of China[21403283] ; Shandong Jiaotong University[00000000] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund[U1501501]
WOS关键词	MOLECULAR-DYNAMICS SIMULATIONS ; RECEPTOR TYROSINE KINASE ; CELL-LUNG-CANCER ; NON-HODGKINS-LYMPHOMA ; HIV-1 PROTEASE ; THERMODYNAMIC INTEGRATION ; MM-PBSA ; LIGAND SELECTIVITY ; TRANSITION PATHWAY ; COMPLEX-FORMATION
WOS研究方向	Chemistry ; Physics
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000415576800056
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272391]
专题	药物发现与设计中心
通讯作者	Chen, Jianzhong; Wang, Jinan
作者单位	1.Shandong Jiaotong Univ, Sch Sci, Jinan 250014, Shandong, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Chen, Jianzhong,Wang, Jinan,Zhu, Weiliang. Mutation L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling[J]. PHYSICAL CHEMISTRY CHEMICAL PHYSICS,2017,19(44):30239-30248.
APA	Chen, Jianzhong,Wang, Jinan,&Zhu, Weiliang.(2017).Mutation L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling.PHYSICAL CHEMISTRY CHEMICAL PHYSICS,19(44),30239-30248.
MLA	Chen, Jianzhong,et al."Mutation L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling".PHYSICAL CHEMISTRY CHEMICAL PHYSICS 19.44(2017):30239-30248.