3D-QSAR and Molecular Docking Studies of Pyrimidine-based EGFR Inhibitors

IF 1.2 4区医学 Q4 CHEMISTRY, MEDICINAL

Letters in Drug Design & Discovery Pub Date : 2023-10-20 DOI:10.2174/0115701808267565231012095231

Hui Gao, Hong Liu, Jingxuan Hou, Qingshan Gu, Meiqi Shi, Qingkun Wu, Lu Zheng

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Abstract

Abstract: Epidermal growth factor tyrosine kinase receptor (EGFR) is expressed in a variety of tumors and has become a new target for anti-cancer drugs. In recent years, small molecule inhibitors targeting EGFR have been reported extensively. In this study, the structure–activity relationship of 119 pyrimidine EGFR inhibitors were studied based on comparative field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMISA). Performant models with high predictive ability were constructed (CoMFA model: q2 = 0.574, r 2 = 0.970, SEE = 0.163, F = 407.252; CoMSIA model: q2 = 0.575, r 2 = 0.968, SEE = 0.171, F = 286.102), according to which 9 new EGFR inhibitors were designed. MD simulation (100 ns) on the docked complex of compound N7 (the most active compound) shows that the small molecule binds with the protein stably. MM/PBSA calculation provided the binding free energy of the compound N7, -37.18 kcal·mol-1, lower than the original ligand. Newly designed molecules showed promising results in ADMET prediction. These results will provide valuable guidance for the design of novel EGFR inhibitors

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基于嘧啶的EGFR抑制剂的3D-QSAR与分子对接研究

摘要表皮生长因子酪氨酸激酶受体(Epidermal growth factor tyrosine kinase receptor, EGFR)在多种肿瘤中表达，已成为抗癌药物的新靶点。近年来，针对EGFR的小分子抑制剂被广泛报道。本研究采用比较场分析(CoMFA)和比较分子相似指数分析(CoMISA)对119种嘧啶类EGFR抑制剂的构效关系进行了研究。构建了具有较高预测能力的绩效模型(CoMFA模型:q2 = 0.574, r 2 = 0.970, SEE = 0.163, F = 407.252;CoMSIA模型:q2 = 0.575, r 2 = 0.968, SEE = 0.171, F = 286.102)，据此设计出9种新的EGFR抑制剂。对化合物N7(活性最强的化合物)的对接物进行了100 ns的MD模拟，结果表明该小分子与蛋白质的结合稳定。MM/PBSA计算得到化合物N7的结合自由能为-37.18 kcal·mol-1，低于原配体。新设计的分子在ADMET预测中显示出良好的结果。这些结果将为新型EGFR抑制剂的设计提供有价值的指导

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来源期刊

Letters in Drug Design & Discovery 医学-医药化学

CiteScore

1.80

自引率

10.00%

发文量

245

审稿时长

3 months

期刊介绍： Aims & Scope Letters in Drug Design & Discovery publishes letters, mini-reviews, highlights and guest edited thematic issues in all areas of rational drug design and discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, and structure-activity relationships. The emphasis is on publishing quality papers very rapidly by taking full advantage of latest Internet technology for both submission and review of manuscripts. The online journal is an essential reading to all pharmaceutical scientists involved in research in drug design and discovery.