Khan Md Shamsuddin Sultan, Majid Amin Malik Shah Abdul, Iqbal Muhammad Adnan, Majid Aman Shah Abdul, Al-Mansoub Majed, Haque Rosenani S M Anwarul
EMAN Cancer Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Pulau Pinang, Malaysia.
The School of Chemical Sciences, Universiti Sains Malaysia (USM), 11800 Penang, Malaysia.
Eur J Pharm Sci. 2016 Oct 10;93:304-18. doi: 10.1016/j.ejps.2016.08.032. Epub 2016 Aug 21.
Glioblastoma multiforme is a highly malignant, heterogenic, and drug resistant tumor. The blood-brain barrier (BBB), systemic cytotoxicity, and limited specificity are the main obstacles in designing brain tumor drugs. In this study a computational approach was used to design brain tumor drugs that could downregulate VEGF and IL17A in glioblastoma multiforme type four. Computational screening tools were used to evaluate potential candidates for antiangiogenic activity, target binding, BBB permeability, and ADME physicochemical properties. Additionally, in vitro cytotoxicity, migration, invasion, tube formation, apoptosis, ROS and ELISA assays were conducted for molecule 6 that was deemed most likely to succeed. The efflux ratio of membrane permeability and calculated docking scores of permeability to glycoproteins (P-gps) were used to determine the BBB permeability of the molecules. The results showed BBB permeation for molecule 6, with the predicted efficiency of 0.55kcal/mol and binding affinity of -37kj/mol corresponding to an experimental efflux ratio of 0.625 and predicted -15kj/mol of binding affinity for P-gps. Molecule 6 significantly affected the angiogenesis pathways by 2-fold downregulation of IL17A and VEGF through inactivation of active sites of HSP90 (predicted binding: -37kj/mol, predicted efficiency: 0.55kcal/mol) and p23 (predicted binding: 12kj/mol, predicted efficiency: 0.17kcal/mol) chaperon proteins. Additionally, molecule 6 activated the 17.38% relative fold of ROS level at 18.3μg/mL and upregulated the caspase which lead the potential synergistic apoptosis through the antiangiogenic activity of molecule 6 and thereby the highly efficacious anticancer upshot. The results indicate that the binding of the molecules to the therapeutic target is not essential to produce a lethal effect on cancer cells of the brain and that antiangiogenic efficiency is much more important.
多形性胶质母细胞瘤是一种高度恶性、异质性且耐药的肿瘤。血脑屏障（BBB）、全身细胞毒性和有限的特异性是设计脑肿瘤药物的主要障碍。在本研究中，采用了一种计算方法来设计可下调4型多形性胶质母细胞瘤中VEGF和IL17A的脑肿瘤药物。使用计算筛选工具来评估抗血管生成活性、靶点结合、血脑屏障通透性和ADME理化性质的潜在候选物。此外，对最有可能成功的分子6进行了体外细胞毒性、迁移、侵袭、管形成、凋亡、ROS和ELISA分析。膜通透性的外排率和计算得出的对糖蛋白（P-糖蛋白）的通透性对接分数用于确定分子的血脑屏障通透性。结果显示分子6具有血脑屏障通透性，预测效率为0.55千卡/摩尔，结合亲和力为-37千焦/摩尔，对应实验外排率为0.625，预测对P-糖蛋白的结合亲和力为-15千焦/摩尔。分子6通过使HSP90（预测结合：-37千焦/摩尔，预测效率：0.55千卡/摩尔）和p23（预测结合：12千焦/摩尔，预测效率：0.17千卡/摩尔）伴侣蛋白的活性位点失活，使IL17A和VEGF下调2倍，从而显著影响血管生成途径。此外，分子6在18.3μg/mL时激活了17.38%的相对ROS水平倍数，并上调了半胱天冬酶，通过分子6的抗血管生成活性导致潜在的协同凋亡，从而产生高效的抗癌效果。结果表明，分子与治疗靶点的结合对于对脑癌细胞产生致死作用并非必不可少，而抗血管生成效率更为重要。
