國家衛生研究院 NHRI:Item 3990099045/10597
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    题名: A molecular modeling-based investigation of the intermolecular interactions between the different Her2 receptor tyrosine kinase mutant variants and clinical small molecules in lung cancer
    作者: Gow, CH;Liu, YC
    贡献者: Division of Biostatistics and Bioinformatics
    摘要: HER2 is a major proliferative driver in lung cancer and the role of HER2-targeting drugs for cancer treatment remains Introduction: unclear. Case series have reported lung adenocarcinoma patients with mutations response to certain tyrosine kinase inhibitors. HER2 However, whether all types of mutations may have similar reposes to anti-HER targeted therapy is yet to be established. HER2 The crystal structure of wild-type HER2 (HER2) kinase domain from the Protein Data Bank database (3PP0) was retrieved. Methods: WT Mutant HER2 amino acids sequences curated from the UniProt database and the sequences were then aligned to each other using ClustalW program. We applied homology remodeling and molecular docking methods to investigate the intermolecular interaction and affinity between variants (wild-type [HER2], A775_G776insYVMA [HER2 ], P780_Y781insGSP [HER2], HER2 WT YVMA GSP A775_V777delG776insLC [HER2],and L755P [HER2 ]) and tyrosine kinase inhibitors (afatinib, lapatinib, and neratinib). LC L755P : We observed that these three inhibitors exhibit differentiated selectivity between the HER2 and HER2 variants. HER2 had Results WT GSP relative lower affinity to lapatinib but was able to sensitize neratinib. HER2 failed to sensitize lapatinib, afatinib, and neratinib. It was YVMA found that HER2 and HER2 cannot sensitize lapatinib and afatinib, but may enhance inhibitory capability of neratinib. Finally, LC L755P afatinib possessed better potency against HER2 than HER2 ; neratinib conferred stronger drug sensitivity to HER2 , HER2, GSP YVMA GSP LC and HER2 , but not HER2 variants. L755P YVMA Different mutant variants may have various reposes to individual tyrosine kinase inhibitors. Understanding of the Conclusion: HER2 HER2 mutant protein—small molecule interactions and factors affecting atomic affinity can be helpful to conduct further research on the rational design of more potent therapeutic agents.
    日期: 2017-05
    關聯: American Journal of Respiratory and Critical Care Medicine. 2017 May;195:A7538.
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1073-449X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000400372507640
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