Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh 13713, Saudi Arabia.
Pathol Res Pract. 2023 Nov;251:154894. doi: 10.1016/j.prp.2023.154894. Epub 2023 Oct 14.
The overexpression of VEGFR-2 receptors in breast cancer provides a valuable approach to anticancer strategies. Targeting VEGFR-2, a new semisynthetic compound (T-1-MCPAB) has been designed.
Computational methods (ADMET, toxicity, DFT, Molecular Docking, Molecular Dynamics Simulations, MM-GBSA, PLIP, and PCAT) were conducted. In addition to the semi-synthesis, in vitro studies (anti-VEGFR-2, anti-proliferative, flow cytometry, and wound scratch assay) were employed.
ADME and toxicity profiles of T-1-MCPAB studies indicated its overall drug-likeness showing results much better than Sorafenib. Then, T-1-MCPAB's exact 3D structure, stability, and reactivity were evoked by the DFT calculations. Molecular docking, molecular dynamics simulations, MM-GPSA, PLIP, and PCAT studies denoted the correct binding and inhibiting potential of T-1-MCPAB, towards VEGFR-2 protein. After the semisynthesis, T-1-MCPAB inhibited VEGFR-2 with an IC of 0.135 µM, which was comparable to sorafenib's IC of 0.0591 µM. T-1-MCPAB also showed a notable performance against MCF7 and T47D breast cancer cell lines with IC values of 30.95 µM and 63.64 µM, respectively, and had high selectivity index values of 3.7 and 1.8, respectively. Furthermore, T-1-MCPAB influenced early and late apoptosis and significantly decreased the potential of MCF7 cells to heal and migrate.
T-1-MCPAB is a promising VEGFR-2 inhibitor with potential for breast cancer treatment. Further chemical and biological studies are needed to explore its potential as a therapeutic agent.
乳腺癌中 VEGFR-2 受体的过表达为抗癌策略提供了有价值的方法。针对 VEGFR-2，设计了一种新的半合成化合物（T-1-MCPAB）。
进行了计算方法（ADMET、毒性、DFT、分子对接、分子动力学模拟、MM-GBSA、PLIP 和 PCAT）。除了半合成之外，还进行了体外研究（抗 VEGFR-2、抗增殖、流式细胞术和划痕实验）。
T-1-MCPAB 的 ADME 和毒性概况研究表明其整体具有药物样特性，结果明显优于索拉非尼。然后，DFT 计算得出 T-1-MCPAB 的精确 3D 结构、稳定性和反应性。分子对接、分子动力学模拟、MM-GPSA、PLIP 和 PCAT 研究表明，T-1-MCPAB 能够正确结合并抑制 VEGFR-2 蛋白。半合成后，T-1-MCPAB 抑制 VEGFR-2 的 IC 为 0.135 µM，与索拉非尼的 IC 为 0.0591 µM相当。T-1-MCPAB 对 MCF7 和 T47D 乳腺癌细胞系也表现出显著的抑制作用，IC 值分别为 30.95 µM 和 63.64 µM，选择性指数值分别为 3.7 和 1.8。此外，T-1-MCPAB 影响早期和晚期凋亡，并显著降低 MCF7 细胞的愈合和迁移能力。
T-1-MCPAB 是一种有前途的 VEGFR-2 抑制剂，具有治疗乳腺癌的潜力。需要进一步的化学和生物学研究来探索其作为治疗剂的潜力。
