设计、合成、对接、MD 模拟及噻吩并[2,3-d]嘧啶衍生物作为新型 EGFR 抑制剂的抗增殖活性评价。

Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-]pyrimidine derivatives as new EGFR inhibitors.

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt.

Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

出版信息

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2220579. doi: 10.1080/14756366.2023.2220579.

A group of EGFR inhibitors derived from thieno[2,3-]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by , the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFR and EGFR, respectively. Compound was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, arrested A549's growth at G1 and G2/M phases. Harmoniously, upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFR and EGFR indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety.

一组源自噻吩并[2,3-]嘧啶核的 EGFR 抑制剂被设计、合成并作为抗增殖的先导化合物进行了研究。 MCF-7 和 A549 细胞系被，最活跃的成员所抑制。它对 EGFR 和 EGFR 的抑制亲和力分别为 37.19 和 204.10 nM。化合物对 WI-38 正常细胞系的安全性比厄洛替尼高 2.5 倍。此外，它在 A549 中表现出诱导早期和晚期细胞凋亡的相当大的潜力。同时，使 A549 的生长在 G1 和 G2/M 期停滞。协调地，与未经处理的 A549 细胞相比，使 BAX 基因上调了 3 倍，使 Bcl-2 基因下调了 3 倍，并使 BAX/Bcl-2 比值增加了 8.3 倍。针对 EGFR 和 EGFR 的分子对接表明了正确的结合模式。此外，MD 模拟在超过 100 ns 的时间内证实了与 EGFR 蛋白的精确结合。最后，进行了各种计算 ADMET 研究，表明具有较高的药物相似性和安全性。