Identification of small-molecule EGFR allosteric inhibitors by high-throughput docking
Identification of small-molecule EGFR allosteric inhibitors by high-throughput docking
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DOI：
10.4155/fmc-2018-0063
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发表时间：
2018-07-01
影响因子：
4.2
通讯作者：
Rastelli, Giulio
中科院分区：
文献类型：
--
作者：
Caporuscio, Fabiana;Tinivella, Annachiara;Rastelli, Giulio
目的：EGFR抑制剂代表了非小细胞肺癌的一线治疗。然而，耐药性的出现迫切需要开发针对耐药突变体的新抑制剂。方法学：最近发布的EGFR激酶结构域与变构抑制剂复合的结构和衍生自其的突变蛋白模型被用于建立用于快速鉴定EGFR变构抑制剂的低成本高通量对接方案。结论：通过对市售化合物的虚拟筛选，鉴定出了感兴趣的新化合物。最有希望的命中被证实是一个新的变构抑制剂的野生型和T790 M/L 858 R双突变EGFR，能够抑制非小细胞肺癌细胞株的生长。[图形]。
Aim: The EGFR inhibitors represent the first-line treatment of non-small-cell lung cancer. However, the emergence of resistance urgently requires the development of new inhibitors targeting drug-resistant mutants. Methodology: A recently released structure of an EGFR kinase domain in complex with an allosteric inhibitor and a mutant protein model derived from it were used to set up a low-cost high-throughput docking protocol for the fast identification of EGFR allosteric inhibitors. Conclusion: The virtual screening of commercially available compounds led to the identification of interesting new hit compounds. The most promising hit was confirmed to be a new allosteric inhibitor of wild-type and T790M/L858R double mutant EGFR which was able to inhibit the growth of non-small-cell lung cancer cell lines.[GRAPHICS].