Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, P.O. Box 400, Al- Ahsa, 31982, Saudi Arabia.
Curr Comput Aided Drug Des. 2021;17(3):421-428. doi: 10.2174/1573409916666200620195025.
The human epidermal growth factor receptor 2 (HER2) plays a role in the propagation of different types of cancers. It was identified in many types of cancer tissues like; breast, ovarian, lung, prostate, and stomach cancers. Therefore, inhibition of HER2 can lead to the discovery of novel anticancer agents.
The study aims to discover a lead scaffold with drug-like properties and high affinity toward HER2.
A list of HER2 inhibitors were collected, analyzed, and subjected to fragmentation and molecular docking. The in silico study computed the affinity, clash score, and ligand entropy score. A pharmacophore model for an ideal inhibitor designed, and tested against breast, lung, and prostatic cancer cell lines.
The discovered lead compound achieved several hydrogen bonds with the primary residues found in the active site of HER2, such as; Met801, Gln99, Lys753, and Thr862 with a computational affinity - 13.45 kcal/mol. In addition to a hydrophobic interaction with leu800. The in vitro cytotoxic activity against; breast cancer MCF-7, prostatic cancer PC-3 and lung cancer A-549 cell lines showed (IC50 = 86.38 ±1.1 mmol/ml), (IC50 = 157.02 ±1.3 mmol/ml), and (IC50 = 181.1 ±2.4 mmol/ml) respectively.
The discovered lead is an excellent drug-like candidate for further development and optimization.
人类表皮生长因子受体 2（HER2）在多种癌症的传播中发挥作用。它在许多类型的癌症组织中被识别，如乳腺癌、卵巢癌、肺癌、前列腺癌和胃癌。因此，抑制 HER2 可以发现新的抗癌药物。
本研究旨在发现一种具有类药性和高亲和力的 HER2 先导骨架。
收集、分析了一系列 HER2 抑制剂，并对其进行了片段化和分子对接。计算了亲和力、碰撞分数和配体熵分数等。设计了理想抑制剂的药效团模型，并对乳腺癌、肺癌和前列腺癌细胞系进行了测试。
所发现的先导化合物与 HER2 活性位点中发现的主要残基（如 Met801、Gln99、Lys753 和 Thr862）形成了多个氢键，计算亲和力为-13.45 kcal/mol。此外，与 leu800 还存在疏水相互作用。对乳腺癌 MCF-7、前列腺癌 PC-3 和肺癌 A-549 细胞系的体外细胞毒性活性分别为（IC50=86.38±1.1 mmol/ml）、（IC50=157.02±1.3 mmol/ml）和（IC50=181.1±2.4 mmol/ml）。
所发现的先导化合物是一种极好的类药候选物，可进一步开发和优化。
