Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS (Deemed to be University), Vile Parle (West), Mumbai, Maharashtra, India.
School of Mathematical Sciences and Institute for Health and Biomedical Innovation, Queensland University of Technology, Gardens Point Campus, Brisbane, Queensland, Australia.
Drug Dev Res. 2019 Sep;80(6):758-777. doi: 10.1002/ddr.21557. Epub 2019 Jun 14.
System x (Sx ), a cystine-glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sx . However, its pharmacological inhibition with novel and potent agents is still very much required due to potential issues, for example, potency, bioavailability, and blood-brain barrier (BBB) permeability, with the current lead molecules such as SSZ. Therefore, in this study, we report the synthesis and structure-activity relationships (SAR) of SSZ derivatives along with molecular docking and dynamics simulations using the developed homology model of xCT chain of Sx antiporter. The generated homology model attempted to address the limitations of previously reported comparative protein models, thereby increasing the confidence in the computational modeling studies. The main objective of the present study was to derive a suitable lead structure from SSZ eliminating its potential issues for the treatment of glioblastoma multiforme (GBM), a deadly and malignant grade IV astrocytoma. The designed compounds with favorable Sx inhibitory activity following in vitro Sx inhibition studies, showed moderately potent cytotoxicity in patient-derived human glioblastoma cells, thereby generating potential interest in these compounds. The xCT-ligand model can be further optimized in search of potent lead molecules for novel drug discovery and development studies.
系统 x（Sx）是一种胱氨酸-谷氨酸反向转运体，已被确立为治疗多种疾病的一个有趣靶点，包括癫痫发作、神经胶质瘤、神经退行性疾病和多发性硬化症。依拉司群、索拉非尼和柳氮磺胺吡啶（SSZ）是几种已确立的 Sx 抑制剂。然而，由于当前的先导分子如 SSZ 存在潜在问题，例如效力、生物利用度和血脑屏障（BBB）通透性，因此仍然非常需要用新型有效的药物来对其进行药理学抑制。因此，在这项研究中，我们报告了 SSZ 衍生物的合成和构效关系（SAR），以及使用开发的 Sx 反向转运体 xCT 链同源模型进行分子对接和动力学模拟。生成的同源模型试图解决先前报道的比较蛋白质模型的局限性，从而提高计算建模研究的可信度。本研究的主要目的是从 SSZ 中得出一种合适的先导结构，以消除其在治疗多形性胶质母细胞瘤（GBM）方面的潜在问题，GBM 是一种致命的恶性四级星形细胞瘤。在体外 Sx 抑制研究中显示出良好的 Sx 抑制活性的设计化合物在患者来源的人胶质母细胞瘤细胞中表现出中等的细胞毒性，从而使这些化合物具有潜在的应用价值。xCT-配体模型可以进一步优化，以寻找用于新型药物发现和开发研究的有效先导分子。
