Computational discovery and validation of 4'-O-methylochnaflavone as a novel HSP90AB1 inhibitor for hepatocellular carcinoma treatment.

IF 3.8 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-10-10 DOI:10.1007/s11030-025-11370-9

Yuan Yang, Xufeng Ning, Ming Chen, Kangle Gao, Tao Guo, Lingshan Zhou, Bin Zeng, Weiwei Zhou

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引用次数: 0

Abstract

Hepatocellular carcinoma (HCC) is a global health issue with limited therapeutic efficacy. Heat shock proteins (HSPs) could enhance adaptation to the oxygen-deprived tumor microenvironment (TME), leading to chemotherapy resistance. Regulating HSP to improve the immune microenvironment may enhance tumor treatment efficacy. However, pharmacological agents targeting HSPs to reverse the immunosuppressive TME remain scarce. In this study, we integrated bioinformatic analysis, virtual screening, molecular docking, molecular dynamics (MD) simulations, and experimental validation to identify therapeutic targets and potential natural product-derived inhibitors. Differentially expressed hypoxia-related immune genes (HRIGs) associated with HCC prognosis were first identified using bioinformatic analysis. Venn diagram revealed HSP90AB1 as the candidate target protein. Virtual screening of the TargetMol and MedChemExpress (MCE) compound libraries was performed, and preliminary molecular docking identified 4'-O-methylochnaflavone as the lead compound. The interaction between 4'-O-methylochnaflavone and HSP90AB1 was further evaluated by MD simulations and experimental validation. Surface plasmon resonance (SPR) assay demonstrated that 4'-O-methylochnaflavone could stably bind HSP90AB1. In vitro CCK-8 assays demonstrated that 4'-O-methylochnaflavone inhibited Hep3B cell proliferation in a time- and dose-dependent manner. Finally, Western blot analysis confirmed hypoxia-induced upregulation of HSP90AB1, which was significantly suppressed by 4'-O-methylochnaflavone. In conclusion, our study identifies 4'-O-methylochnaflavone is a promising HSP90AB1-targeting therapeutic candidate for HCC treatment.

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计算发现和验证4'- o -甲基萘醌作为治疗肝细胞癌的新型HSP90AB1抑制剂。

肝细胞癌（HCC）是一个全球性的健康问题，治疗效果有限。热休克蛋白（HSPs）可以增强对缺氧肿瘤微环境（TME）的适应，导致化疗耐药。调节热休克蛋白改善免疫微环境可提高肿瘤治疗效果。然而，靶向热休克蛋白逆转免疫抑制TME的药理学药物仍然很少。在这项研究中，我们将生物信息学分析、虚拟筛选、分子对接、分子动力学（MD）模拟和实验验证相结合，以确定治疗靶点和潜在的天然产物衍生抑制剂。差异表达的缺氧相关免疫基因（hrig）与HCC预后相关，首次通过生物信息学分析确定。维恩图显示HSP90AB1为候选靶蛋白。对TargetMol和MedChemExpress （MCE）化合物文库进行虚拟筛选，初步分子对接确定4′- o -甲基萘醌为先导化合物。通过MD模拟和实验验证进一步评价了4′- o -甲基萘醌与HSP90AB1的相互作用。表面等离子体共振（SPR）实验表明，4′- o -甲基萘醌能稳定结合HSP90AB1。体外CCK-8实验表明，4′- o -甲基萘酮抑制Hep3B细胞增殖呈时间和剂量依赖性。最后，Western blot分析证实缺氧诱导HSP90AB1表达上调，4′- o -甲基甲氧基钠酮显著抑制HSP90AB1表达。总之，我们的研究确定了4'- o -甲基甲基黄酮是一种有希望的靶向hsp90ab1的HCC治疗候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;