通过分子对接、动力学模拟和体外研究确定治疗癌症的次黄嘌呤-鸟嘌呤磷酸核糖基转移酶潜在抑制剂。

IF 2.3 3区 环境科学与生态学 Q3 CHEMISTRY, MULTIDISCIPLINARY
O Afzal, A Altharawi, M A Alamri
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引用次数: 0

摘要

次黄嘌呤鸟嘌呤磷酸核糖基转移酶1 (HPRT1)是一种突变生物标志物和管家人类报告基因,主要用于评估与癌症发展相关的突变频率。在这项研究中,我们的目的是利用集成的计算机方法,鉴定HPRT1基因编码的人次黄嘌呤鸟嘌呤磷酸核糖基转移酶(HPRT)蛋白的潜在抑制剂。从IMPPAT 2.0数据库17,967种植物化学物质库中进行类药性筛选,并进行分子对接,最终筛选出排名前20位的植物化学物质。进一步的相互作用谱显示,IMPHY008718 (Gibberellin A34)和IMPHY011650 (Chasmanthin)结合在HPRT1蛋白的GMP结合位点。所选化合物的ADMET特性和生物学功能预测表明它们具有抗癌潜力。对IMPHY008718和IMPHY011650对接配合物进行了200 ns MD模拟。除了主成分、自由能和MM/PBSA分析外,还进行了综合MD轨迹分析。此外,体外人HPRT抑制实验证实并揭示了与标准抑制剂HGPRT/TBrHGPRT1-IN-1 (Ki 0.032µM)相比,Gibberellin A34 (Ki 0.121µM)和Chasmanthin (Ki 0.368µM)的抑制潜力。总的来说,这些结果强烈建议进一步的实验工作,将这些基于植物的分子作为抗癌药物开发的人类HPRT抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of potential inhibitors of hypoxanthine-guanine phosphoribosyl transferase for cancer treatment by molecular docking, dynamics simulation and in vitro studies.

Hypoxanthine guanine phosphoribosyltransferase 1 (HPRT1) is a mutational biomarker and a housekeeping human reporter gene that is predominantly employed to assess mutation frequencies associated with cancer development. In this study, our purpose was to identify potential inhibitors against the human hypoxanthine guanine phosphoribosyltransferase (HPRT) protein encoded by HPRT1 gene by employing an integrated in silico approach. The library of 17,967 phytochemicals (IMPPAT 2.0 database) was screened for drug-like properties followed by molecular docking, resulting in the selection of top 20 phytochemicals. Further interaction profile revealed that IMPHY008718 (Gibberellin A34) and IMPHY011650 (Chasmanthin) binds at the GMP binding site of the HPRT1 protein. ADMET properties and biological function predictions of the selected compounds indicate their anticancer potential. Both IMPHY008718 and IMPHY011650 docked complexes were examined in 200 ns MD simulations. Comprehensive MD trajectory analysis was performed in addition to principal component, free energy and MM/PBSA analysis. Furthermore, in vitro human HPRT inhibition assay confirmed and revealed inhibitory potential for Gibberellin A34 (Ki 0.121 µM) and Chasmanthin (Ki 0.368 µM), as compared to standard inhibitor, HGPRT/TBrHGPRT1-IN-1 (Ki 0.032 µM). Overall, these results strongly recommend further experimental work concerning these plant-based molecules as human HPRT inhibitors for anticancer drug development.

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来源期刊
CiteScore
5.20
自引率
20.00%
发文量
78
审稿时长
>24 weeks
期刊介绍: SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.
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