Yang Wenzhuo, Wang Shengnan, Zhang Xiangmao, Sun Hu, Zhang Menghan, Chen Hongyu, Cui Junxiang, Li Jinyang, Peng Fei, Zhu Mingqin, Yu Bingcheng, Li Yifan, Yang Liu, Min Wanwan, Xue Mengru, Pan Lin, Zhu Hao, Wu Bo, Gu Yinghao
Department of Neurosurgery, Zibo Central Hospital, Zibo, China.
Department of Neurosurgery, Cancer Hospital of Sun Yat-sen University, Guangzhou, China.
Front Neurosci. 2023 Jan 4;16:1060012. doi: 10.3389/fnins.2022.1060012. eCollection 2022.
High-grade glioma (HGG) is a malignant brain tumor that is common and aggressive in children and adults. In the current medical paradigm, surgery and radiotherapy are the standard treatments for HGG patients. Despite this, the overall prognosis is still very bleak. Studies have shown that platelet-derived growth factor receptor α (PDGFRA) is an essential target to treat tumors and inhibiting the activity of PDGFRA can improve the prognosis of HGG. Thus, PDGFRA inhibitors are critical to developing drugs and cancer treatment.
The purpose of this study was to screen lead compounds and candidate drugs with potential inhibitors against platelet-derived growth factor receptor α (PDGFRA) from the drug library (ZINC database) in order to improve the prognosis of patients with high-grade glioma (HGG).
In our study, we selected Imatinib as the reference drug. A series of computer-aided technologies, such as Discovery Studio 2019 and Schrodinger, were used to screen and assess potential inhibitors of PDGFRA. The first step was to calculate the LibDock scores and then analyze the pharmacological and toxicological properties. Following this, we docked the small molecules selected in the previous steps with PDGFRA to study their docking mechanism and affinity. In addition, molecular dynamics simulation was used to determine whether the ligand-PDGFRA complex was stable in nature.
Two novel natural compounds 1 and 2 (ZINC000008829785 and ZINC000013377891) from the ZINC database were found binding to PDGFRA with more favorable interaction energy. Also, they were predicted with less Ames mutagenicity, rodent carcinogenicity, non-developmental toxic potential, and tolerant with cytochrome P450 2D6 (CYP2D6). The dynamic simulation analysis demonstrated that ZINC000008829785-PDGFRA and ZINC000013377891-PDGFRA dimer complex had more favorable potential energy compared with Imatinib, and they can exist in natural environments stably.
ZINC000008829785 and ZINC000013377891 might provide a solid foundation for drugs that inhibit PDGFRA in HGG. In addition to being safe drug candidates, these compounds had important implications for improving drugs targeting PDGFRA.
高级别胶质瘤（HGG）是一种常见且侵袭性强的儿童及成人大脑恶性肿瘤。在当前医学模式下，手术和放疗是HGG患者的标准治疗方法。尽管如此，总体预后仍然非常严峻。研究表明，血小板衍生生长因子受体α（PDGFRA）是治疗肿瘤的关键靶点，抑制PDGFRA的活性可改善HGG的预后。因此，PDGFRA抑制剂对于药物研发和癌症治疗至关重要。
本研究旨在从药物库（ZINC数据库）中筛选具有潜在抑制血小板衍生生长因子受体α（PDGFRA）作用的先导化合物和候选药物，以改善高级别胶质瘤（HGG）患者的预后。
在本研究中，我们选择伊马替尼作为参考药物。运用一系列计算机辅助技术，如Discovery Studio 2019和Schrodinger，对PDGFRA的潜在抑制剂进行筛选和评估。第一步是计算LibDock分数，然后分析其药理和毒理性质。在此之后，我们将上一步中筛选出的小分子与PDGFRA进行对接，以研究它们的对接机制和亲和力。此外，利用分子动力学模拟来确定配体 - PDGFRA复合物在自然环境中是否稳定。
从ZINC数据库中发现两种新型天然化合物1和2（ZINC000008829785和ZINC000013377891）与PDGFRA结合时具有更有利的相互作用能。此外，预测它们具有较低的艾姆斯致突变性、啮齿动物致癌性、非发育毒性潜力，并且对细胞色素P450 2D6（CYP2D6）具有耐受性。动态模拟分析表明，与伊马替尼相比，ZINC000008829785 - PDGFRA和ZINC000013377891 - PDGFRA二聚体复合物具有更有利的势能，并且它们可以在自然环境中稳定存在。
ZINC000008829785和ZINC000013377891可能为HGG中抑制PDGFRA的药物提供坚实基础。除了是安全的候选药物外，这些化合物对于改进靶向PDGFRA的药物具有重要意义。
