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虚拟查,分子动力学模拟和生物活性评估验证T13074作为双位EGFR/c-Met抑制剂

Dang Fan¹, Haifeng Dong¹, Anqi Li¹

¹School of Pharmacy, Jiangxi Science & Technology Normal University, China.

Current medicinal chemistry

|June 26, 2024

概括

这项研究确定T13074是对EGFR/c-Met的强有力的双抑制剂,显示出显著的抗瘤活性. 它提供了一种有希望的策略来克服由EGFR中的L858R/T790M突变引起的耐药性.

科学领域:

药用化学医学化学
分子生物学分子生物学
在瘤学瘤学.

背景情况:

对表皮生长因子受体 (EGFR) 抑制剂的耐药性,特别是由于L858R/T790M突变,构成了重大的临床挑战.
开发针对EGFR和c-Met的双抑制剂是一种有前途的战略,可以克服获得的耐药性并提高治疗疗效.

研究的目的:

确定有效对抗EGFR/c-Met的新型双抑制剂,重点是克服L858R/T790M诱导的耐药性.
评估有希望的候选化合物的体外抗瘤活性和分子机制.

主要方法:

使用虚拟查和集群分析,从化合物库中识别潜在的双抑制剂.
进行了包括MTT,激酶抑制,AO染色和JC-1在内的体外试验,以评估抗瘤活性和亡诱导.
进行了分子对接和分子动力学模拟,以阐明化合物与EGFR和c-Met蛋白的结合相互作用.

主要成果:

化合物T13074对EGFRL858R/T790M激酶 (IC50 = 2.446 μM) 和c-Met激酶 (IC50 = 7.401 nM) 均表现出强大的抑制活性.
T13074对H1975细胞表现出显著的抗瘤作用 (IC50 = 1.93 μM),并以度依赖的方式诱导了亡.
分子模拟显示,T13074与EGFR (-90.329 ± 16.680 kJ/mol) 和c-Met (-139.935 ± 17.414 kJ/mol) 都具有有利的结合能.

结论:

T13074在体外表现出强大的抗瘤活性,并作为EGFR/c-Met的双抑制剂.
该化合物显示出克服由L858R/T790M突变媒介的EGFR耐药性的显著潜力.
T13074是治疗由EGFR和c-Met信号驱动的耐药癌症的有希望的治疗候选药物.

关键词:

由于EGFR的耐药性,所以我们可以使用它.基于ROC的虚拟选生物活动评估评估生物活动评估.在c-Met Met中使用.发现药物的发现.动态模拟. 动态模拟.

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