Lung cancer remains the leading and deadly type of cancer worldwide. It was estimated to account for about 25% of the 7 million people that died as a result of cancer-related issues/mortality every year in the world. Non-small cell lung cancer (NSCLC) is the lethal/deadly class of lung cancer with nearly 1.5 million reported cases and less than 20% survival rate. Therefore, it becomes necessary to explore more effective NSCLC drugs. A computational approach was employed here to design ten new EGFRWT inhibitors using compound 18 as a template for the design identified with the best binding affinity and good pharmacokinetic properties previously reported in our work. The modeled inhibitory activities of these newly designed EGFRWT inhibitors (range from 7.746966 to 11.09261) were better than that of the hit compound with pIC50 of 7.5639 and gefitinib the positive control with pIC50 of 5.879426. The ligand-binding interaction between these newly designed EGFRWT inhibitors and the EGFR tyrosine kinase receptor as shown in Table 3 was investigated and elucidated using molecular docking protocol. Based on the molecular docking results, the binding affinities of these newly designed EGFRWT inhibitors were found to be between − 8.8 and − 9.5 kcal/mol. The designed compound SFD10 has the highest binding affinity of − 9.5 kcal/mol followed by compound SFD8 (with a binding affinity of − 9.3 kcal/mol), then by compound SFD9 and 4 (each with a binding affinity of − 9.3 kcal/mol). None of them was found to have more than one violation of the filtering criterion used in this study thereby showing good ADMET properties. The modeled inhibitory activities and binding affinities of these newly designed EGFRWT inhibitors were found to be higher than that of the template compound and the control (gefitinib) used in this research. They were also seen to be non-toxic with good pharmacokinetic properties.

中文翻译：

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设计更有效的喹唑啉衍生物作为 EGFR ^WT抑制剂用于治疗 NSCLC：一种计算方法

肺癌仍然是世界范围内主要和致命的癌症类型。据估计，全世界每年因癌症相关问题/死亡率而死亡的 700 万人中，约有 25% 是癌症。非小细胞肺癌 (NSCLC) 是致命/致命的肺癌类别，报告病例近 150 万，存活率低于 20%。因此，有必要探索更有效的非小细胞肺癌药物。此处采用计算方法设计十种新的 EGFRWT 抑制剂，使用化合物 18 作为设计模板，该设计具有先前在我们工作中报道的最佳结合亲和力和良好的药代动力学特性。这些新设计的 EGFRWT 抑制剂的模拟抑制活性（范围从 7.746966 到 11.09261）优于 pIC50 为 7 的命中化合物。5639 和吉非替尼是阳性对照，pIC50 为 5.879426。这些新设计的 EGFRWT 抑制剂与 EGFR 酪氨酸激酶受体之间的配体结合相互作用如表 3 所示，使用分子对接方案进行了研究和阐明。根据分子对接结果，发现这些新设计的 EGFRWT 抑制剂的结合亲和力介于 - 8.8 和 - 9.5 kcal/mol 之间。设计的化合物 SFD10 的结合亲和力最高，为 − 9.5 kcal/mol，其次是化合物 SFD8（结合亲和力为 − 9.3 kcal/mol），然后是化合物 SFD9 和 4（每个结合亲和力为 − 9.3 kcal/mol ）。发现它们中没有一个违反本研究中使用的过滤标准，从而显示出良好的 ADMET 特性。发现这些新设计的 EGFRWT 抑制剂的模拟抑制活性和结合亲和力高于本研究中使用的模板化合物和对照（吉非替尼）。它们还被认为是无毒的，具有良好的药代动力学特性。