New natural compound inhibitors of PDGFRA (platelet-derived growth factor receptor α) based on computational study for high-grade glioma therapy

被引:4
|
作者
Yang, Wenzhuo [1 ,2 ]
Wang, Shengnan [3 ]
Zhang, Xiangmao [1 ]
Sun, Hu [1 ]
Zhang, Menghan [4 ]
Chen, Hongyu [2 ]
Cui, Junxiang [5 ]
Li, Jinyang [5 ]
Peng, Fei [6 ]
Zhu, Mingqin [3 ]
Yu, Bingcheng [7 ]
Li, Yifan [7 ]
Yang, Liu [8 ]
Min, Wanwan [3 ]
Xue, Mengru [3 ]
Pan, Lin [9 ]
Zhu, Hao [10 ]
Wu, Bo [11 ]
Gu, Yinghao [1 ]
机构
[1] Zibo Cent Hosp, Dept Neurosurg, Zibo, Peoples R China
[2] Sun Yat Sen Univ, Canc Hosp, Dept Neurosurg, Guangzhou, Peoples R China
[3] First Hosp Jilin Univ, Dept Neurol, Changchun, Peoples R China
[4] Xinxiang Med Coll, Affiliated Hosp 5, Dept Clin Lab, Xinxiang, Peoples R China
[5] Weifang Med Univ, Sch Clin Med, Weifang, Peoples R China
[6] Baylor Coll Med, Dept Med, Div Endocrinol Diabet & Metab, Houston, TX USA
[7] Sun Yat Sen Univ, Zhongshan Sch Med, Guangzhou, Peoples R China
[8] First Hosp Jilin Univ, Dept Neurosurg Oncol, Changchun, Peoples R China
[9] Jilin Univ, Sch Clin Med, Changchun, Peoples R China
[10] First Hosp Jilin Univ, Dept Hepatol, Changchun, Peoples R China
[11] First Hosp Jilin Univ, Dept Orthopaed, Changchun, Peoples R China
关键词
high-grade glioma; PDGFRA; natural products; Imatinib; virtual screening; PEDIATRIC HIGH-GRADE; RECURRENT GLIOBLASTOMA; ADJUVANT TEMOZOLOMIDE; TYROSINE-KINASES; BRAIN-STEM; SURVIVAL; IMATINIB; GENES; RADIOTHERAPY; CONCOMITANT;
D O I
10.3389/fnins.2022.1060012
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
BackgroundHigh-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 alpha (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. ObjectiveThe purpose of this study was to screen lead compounds and candidate drugs with potential inhibitors against platelet-derived growth factor receptor alpha (PDGFRA) from the drug library (ZINC database) in order to improve the prognosis of patients with high-grade glioma (HGG). Materials and methodsIn 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. ResultsTwo 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. ConclusionZINC000008829785 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.
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页数:14
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