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Mechanistic Study of Potent Fluorinated EGFR Kinase Inhibitors with a Quinazoline Scaffold against L858R/T790M/C797S Resistance Mutation: Unveiling the Fluorine Substituent Cooperativity Effect on the Inhibitory Activity.
The Journal of Physical Chemistry B ( IF 3.3 ) Pub Date : 2020-06-30 , DOI: 10.1021/acs.jpcb.0c03440
Farideh Badichi Akher 1, 2 , Abdolkarim Farrokhzadeh 3 , Neil Ravenscroft 2 , Michelle M Kuttel 1
Affiliation  

Fluorination has considerable potential with regard to the design of kinase inhibitors for anticarcinoma therapy. It was recently reported that fluorination increases the potency of inhibitors of the epidermal growth factor receptor (EGFR), mutations of which have been linked specifically to nonsmall-cell lung cancer. For the L858R/T790M/C797S triplet mutant (EGFRTM), a difluorinated inhibitor, 25g, was found to have 4.23 times greater potency against the EGFRTM than an unfluorinated inhibitor, 25a. This discovery necessitates a rational explanation for the underlying inhibitory mechanisms. Here, we apply multiple computational approaches to explore, validate, and differentiate the binding modes of 25a and 25g in the EGFRTM and investigate the cooperativity effect of fluorine substituents on the inhibitory activity. Our results showed that the EGFRTM in the presence of 25g undergoes a series of conformational changes that favor inhibitor binding to both the active and allosteric sites. Further, the cooperativity effect of fluorine substituents is positive: the complex stability is increased by each additional fluorine substituent. Estimated binding free energies show good correlation with the experimental biological activity. Subsequently, the decomposition energy analysis revealed that the van der Waals interaction is the principal force contributing to variations in the binding affinities of 25a and 25g to the EGFRTM. Per-residue energy-based hierarchical clustering analysis suggests that three hot-spot residues, L718, K745, and D855, are the key in achieving optimal binding modes for 25g with higher affinity in the EGFRTM compared to 25a. This study provides a rationale for the superior EGFRTM-inhibitory potency exhibited by 25g over 25a, which is expected to be useful for the future rational structure-based design of novel EGFRTM inhibitors with improved potency and selectivity.

中文翻译:

喹唑啉支架对L858R / T790M / C797S抗性突变的有效氟化EGFR激酶抑制剂的机理研究:揭示氟取代基的协同作用对抑制活性的影响。

就用于抗癌治疗的激酶抑制剂的设计而言,氟化具有相当大的潜力。最近报道,氟化作用增加了表皮生长因子受体(EGFR)抑制剂的效力,该抑制剂的突变与非小细胞肺癌特别相关。对于L858R / T790M / C797S突变体的三重(EGFR TM),一个二氟化的抑制剂,25克,被发现具有抗EGFR 4.23倍更大的效力TM比未氟化抑制剂,25A。这一发现有必要对潜在的抑制机制做出合理的解释。在这里,我们采用多种计算方法来探索,验证和区分25a在EGFR TM中加入25g,研究氟取代基对抑制活性的协同作用。我们的结果表明,在25g存在下的EGFR TM经历了一系列构象变化,有利于抑制剂与活性位点和变构位点的结合。此外,氟取代基的协同作用是正的:每个另外的氟取代基均增加了络合物的稳定性。估计的结合自由能显示出与实验生物活性的良好相关性。随后,分解能分析表明范德华相互作用是导致25a25g结合亲和力变化的主力。到EGFR TM。基于每个残基能量的层次聚类分析表明,三个热点残基L718,K745和D855是获得25g最佳结合模式的关键,与25a相比,它们在EGFR TM中具有更高的亲和力。这项研究为25g超过25a表现出的优异的EGFR TM抑制效能提供了理论依据,预期该方法可用于未来基于合理结构的新型EGFR TM抑制剂的合理设计,具有更高的效能和选择性。
更新日期:2020-07-16
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