Chemotherapy Drug Response to the L858R-induced Conformational Change of EGFR Activation Loop in Lung Cancer

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• 作者：Xi Ding ; Xingcai Liu ; Xiaoyun Song and Jun Yao
• 刊名：Molecular Informatics
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：35
• 期：10
• 页码：529-537
• 全文大小：1617K
• ISSN：1868-1751

文摘

Oncogenic L858R mutation of human epidermal growth factor receptor (EGFR) confers constitutive activation to the kinase and is frequently observed in the pathological process of metastatic lung cancer. Selective inhibition of EGFR^L858R mutant over wild-type EGFR (EGFR^WT) has been established as an attractive target for cancer chemotherapy. Here, we performed long-term molecular dynamics (MD) simulations to reconstruct the complete dynamics trajectory of L858R-induced conformational change in EGFR activation loop (A-loop). It was found that the mutation considerably destabilizes A-loop in Src-like inactive conformation and promotes the loop conversion to DFG-in active form. Electrostatic force is primarily responsible for the conversion and stabilization upon the mutation. Binding free energy analysis revealed that Gefitinib exhibits strong selectivity for mutant over wild-type kinases. The A-loop conformation, but not L858R mutation, directly determines inhibitor affinity; the mutation can indirectly influence inhibitor binding via regulation of A-loop conformation. Subsequently, chemical similarity searching was carried out with the structural sketch of Gefitinib against a large library of drug/lead-like compounds, from which two hits were identified to have high selectivity for EGFR^L858R over EGFR^W; they can potently inhibit the kinase mutant with IC₅₀ values at nanomolar level. The selectivity is primarily originated from hydrogen bond interactions of inhibitor ligands with mutant but not with wild type due to the A-loop conformational difference.