The discovery of epidermal growth factor receptor (EGFR) inhibitors for the treatment of lung cancer, most especially non-small cell lung cancer (NSCLC), was one of the major challenges encountered by the medicinal chemist in the world. The treatment of EGFR tyrosine kinase to manage NSCLCs becomes an urgent therapeutic necessity. NSCLC was the foremost cause of cancer mortality worldwide. Therefore, there is a need to develop more EGFR inhibitors due to the development of drug resistance by the mutation. This research is aimed at designing new EGFR inhibitors using a structure-based design approach. Structure-based drug design comprises several steps such as protein structure retrieval and preparation, ligand library preparation, docking, and structural modification on the best hit compound to design new ones. Molecular docking virtual screening on fifty sets of quinazoline derivatives/epidermal growth factor receptor inhibitors against their target protein (EGFR tyrosine kinase receptor PDB entry: 3IKA) and pharmacokinetic profile predictions were performed to identify hit compounds with promising affinities toward their target and good pharmacokinetic profiles. The hit compounds identified were compound 6 with a binding affinity of − 9.3 kcal/mol, compounds 5 and 8, each with a binding affinity of − 9.1 kcal/mol, respectively. The three hit compounds bound to EGFR tyrosine kinase receptor via four different types of interactions which include conventional hydrogen bond, carbon-hydrogen bond, electrostatic, and hydrophobic interactions, respectively. The best hit (compound 6) among the 3 hit compounds was retained as a template and used to design sixteen new EGFR inhibitors. The sixteen newly designed compounds were also docked into the active site of EGFR tyrosine kinase receptor to study their mode of interactions with the receptor. The binding affinities of these newly designed compounds range from − 9.5 kcal/mol to − 10.2 kcal/mol. The pharmacokinetic profile predictions of these newly designed compounds were further examined and found to be orally bioavailable with good absorption, low toxicity level, and permeable properties. The sixteen newly designed EGFR inhibitors were found to have better binding affinities than the template used in the designing process and afatinib the positive control (an FDA approved EGFR inhibitor). None of these designed compounds was found to violate more than the permissible limit set by RO5. More so, the newly designed compounds were found to have good synthetic accessibility which indicates that these newly designed compounds can be easily synthesized in the laboratory.

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一些喹唑啉衍生物作为表皮生长因子受体抑制剂的基于结构的设计

用于治疗肺癌，尤其是非小细胞肺癌（NSCLC）的表皮生长因子受体（EGFR）抑制剂的发现是世界药物化学家面临的主要挑战之一。治疗 EGFR 酪氨酸激酶以治疗 NSCLC 成为迫切的治疗需求。NSCLC 是全球癌症死亡的首要原因。因此，由于突变产生耐药性，需要开发更多的EGFR抑制剂。这项研究旨在使用基于结构的设计方法设计新的 EGFR 抑制剂。基于结构的药物设计包括蛋白质结构检索和制备、配体库制备、对接和对最佳命中化合物进行结构修饰以设计新化合物等几个步骤。对 50 组喹唑啉衍生物/表皮生长因子受体抑制剂针对其靶蛋白（EGFR 酪氨酸激酶受体 PDB 条目：3IKA）进行分子对接虚拟筛选和药代动力学特征预测，以鉴定对靶标具有良好亲和力和良好药代动力学特征的命中化合物. 鉴定的命中化合物是结合亲和力为 - 9.3 kcal/mol 的化合物 6、化合物 5 和 8，分别具有 - 9.1 kcal/mol 的结合亲和力。这三种命中化合物分别通过四种不同类型的相互作用与 EGFR 酪氨酸激酶受体结合，包括常规氢键、碳氢键、静电和疏水相互作用。3 种命中化合物中的最佳命中（化合物 6）被保留为模板，用于设计 16 种新的 EGFR 抑制剂。16 种新设计的化合物还停靠在 EGFR 酪氨酸激酶受体的活性位点，以研究它们与受体的相互作用模式。这些新设计的化合物的结合亲和力范围从 - 9.5 kcal/mol 到 - 10.2 kcal/mol。进一步研究了这些新设计化合物的药代动力学特征预测，发现它们具有良好的吸收性、低毒性和渗透性，具有口服生物可利用性。发现 16 种新设计的 EGFR 抑制剂具有比设计过程中使用的模板和阿法替尼作为阳性对照（FDA 批准的 EGFR 抑制剂）更好的结合亲和力。没有发现这些设计的化合物违反了 RO5 设定的允许限值。更重要的是，发现新设计的化合物具有良好的合成可及性，这表明这些新设计的化合物可以在实验室中轻松合成。