Sonar Priyanka, Shaikh Karimunnisa, Ballav Sangeeta, Basu Soumya, Harer Sunil
Department of Pharmaceutics, Progressive Education Society's, Modern College of Pharmacy, Nigdi, Pune, M.S, India.
Cancer and Translational Research Laboratory, Dr. D.Y. Patil Biotechnology and Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Tathawade, Pune, M.S, India.
Bioinformation. 2022 Oct 31;18(10):974-981. doi: 10.6026/97320630018974. eCollection 2022.
Tyrosine kinase receptors promote the growth and differentiation of normal breast and malignant human breast cancer cells, known as ERBB receptors. Various ERBB receptors are EGFR/ErbB1 and ErbB2/neu, which get over expressed in different solid tumors that activate upon binding of ligand to the extra cellular domain of these receptors. Of note, the epidermal growth factor receptor (EGFR) is a prime contributor to cancer through the involvement of four receptor tyrosine kinases (RTKs), namely, HER1, HER2, HER3, and HER4. Among them, HER2 and HER4 are majorly associated with breast cancer. Non-peptide quinazoline compounds homologous of the adenosine triphosphate (ATP) are competitively inhibited to RTKs to prevent cancer growth and metastasis. Various small drug molecule that targets the RTKs having the same scaffold, includes Lapatinib, Tivozanib, Erlotinib, Gefitinib, Crizotinib, and Ceritinib. The present study aims to investigate the comparative potential of structurally similar TKIs against HER2 and HER4 receptor receptors-silico molecular docking using FlexX software (LeadIT 2.3.2). Each docked complex's interaction profile was performed using BIOVIA Discovery Studio Visualizer 4.0. Molecular docking analysis was performed in order to get deeper insights into the interaction and binding pattern of the ligands with HER2 and HER4 receptors. The docking results revealed the Lapatinib compound acquired the relatively highest binding score of -32.36 kcal/mol and -35.76 kcal/mol with HER2 and HER4 proteins, respectively, concerning other compounds. Lapatinib is identified as a potential inhibitor for both the RTKs. Our study thus suggests the probable direction that could be further explored in inhibiting EGFR protein harboring breast cancer.
酪氨酸激酶受体可促进正常乳腺细胞和人恶性乳腺癌细胞的生长与分化，这类受体被称为ERBB受体。各种ERBB受体包括EGFR/ErbB1和ErbB2/neu，它们在不同实体瘤中过度表达，在配体与这些受体的细胞外结构域结合后被激活。值得注意的是，表皮生长因子受体（EGFR）通过四种受体酪氨酸激酶（RTK），即HER1、HER2、HER3和HER4参与癌症发生，其中HER2和HER4与乳腺癌主要相关。与三磷酸腺苷（ATP）同源的非肽喹唑啉化合物可竞争性抑制RTK，以防止癌症生长和转移。各种靶向具有相同支架结构的RTK的小分子药物，包括拉帕替尼、替沃扎尼、厄洛替尼、吉非替尼、克唑替尼和色瑞替尼。本研究旨在使用FlexX软件（LeadIT 2.3.2）研究结构相似的酪氨酸激酶抑制剂（TKI）针对HER2和HER4受体的比较潜力，通过计算机辅助分子对接进行研究。使用BIOVIA Discovery Studio Visualizer 4.0对每个对接复合物的相互作用图谱进行分析。进行分子对接分析是为了更深入地了解配体与HER2和HER4受体的相互作用及结合模式。对接结果显示，与其他化合物相比，拉帕替尼化合物与HER2和HER4蛋白的结合得分相对最高，分别为-32.36 kcal/mol和-35.76 kcal/mol。拉帕替尼被确定为两种RTK的潜在抑制剂。因此，我们的研究为抑制携带EGFR蛋白的乳腺癌的进一步探索指明了可能的方向。
