A structure-based approach to discover a potential isomerase Pin1 inhibitor for cancer therapy using computational simulation and biological studies

IF 2.6 4区生物学 Q2 BIOLOGY

Computational Biology and Chemistry Pub Date : 2024-11-22 DOI:10.1016/j.compbiolchem.2024.108290

Wang Wang , Qizhou Jiang , Jiaxin Tao , Zhenxian Zhang , GuoPing Liu , Binxuan Qiu , Qingyang Hu , Yuxi Zhang , Chao Xie , Jiawen Song , GuoZhen Jiang , Hui Zhong , Yanling Zou , Jiaqi Li , Shaoli lv

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引用次数: 0

Abstract

Peptidyl-prolyl cis/trans isomerase Pin1 occupies a prominent role in preventing the development of certain malignant tumors. Pin1 is considered a target for the treatment of related malignant tumors, so the identification of novel Pin1 inhibitors is particularly urgent. In this study, we preliminarily predicted eight candidates from FDA-approved drug database as the potential Pin1 inhibitors through virtual screening combined with empirical screening. Therefore, we selected these eight candidates and tested their binding affinity and inhibitory activity against Pin1 using fluorescence titration and PPIase activity assays, respectively. Subsequently, we found that four FDA-approved drugs showed good binding affinities and inhibition effects. In addition, we also observed that bexarotene can reduce cell viability in a dose-dependent and time-dependent manner and induce apoptosis. Finally, we inferred that residues K63, R68 and R69 are important in the binding process between bexarotene and Pin1. All in all, repurposing of FDA-approved drugs to inhibit Pin1 may provide a promising insight into the identification and development of new treatments for certain malignant tumors.

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基于结构的方法，利用计算模拟和生物学研究发现潜在的癌症治疗异构酶 Pin1 抑制剂

肽基脯氨酰顺式/反式异构酶 Pin1 在防止某些恶性肿瘤的发生发展方面发挥着重要作用。Pin1被认为是治疗相关恶性肿瘤的靶点，因此鉴定新型Pin1抑制剂尤为迫切。在本研究中，我们通过虚拟筛选和经验筛选相结合的方法，从美国 FDA 批准的药物数据库中初步预测了 8 个候选药物作为潜在的 Pin1 抑制剂。因此，我们选择了这八种候选药物，并分别使用荧光滴定法和 PPIase 活性测定法测试了它们与 Pin1 的结合亲和力和抑制活性。随后，我们发现四种美国 FDA 批准的药物表现出良好的结合亲和力和抑制效果。此外，我们还观察到贝沙罗汀能以剂量依赖性和时间依赖性的方式降低细胞活力并诱导细胞凋亡。最后，我们推断残基 K63、R68 和 R69 在贝沙罗汀与 Pin1 的结合过程中起着重要作用。总而言之，将美国食品及药物管理局批准的药物重新用于抑制 Pin1 可能会为确定和开发某些恶性肿瘤的新疗法提供一个很好的视角。

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

Computational Biology and Chemistry 生物-计算机：跨学科应用

CiteScore

6.10

自引率

3.20%

发文量

142

审稿时长

24 days

期刊介绍： Computational Biology and Chemistry publishes original research papers and review articles in all areas of computational life sciences. High quality research contributions with a major computational component in the areas of nucleic acid and protein sequence research, molecular evolution, molecular genetics (functional genomics and proteomics), theory and practice of either biology-specific or chemical-biology-specific modeling, and structural biology of nucleic acids and proteins are particularly welcome. Exceptionally high quality research work in bioinformatics, systems biology, ecology, computational pharmacology, metabolism, biomedical engineering, epidemiology, and statistical genetics will also be considered. Given their inherent uncertainty, protein modeling and molecular docking studies should be thoroughly validated. In the absence of experimental results for validation, the use of molecular dynamics simulations along with detailed free energy calculations, for example, should be used as complementary techniques to support the major conclusions. Submissions of premature modeling exercises without additional biological insights will not be considered. Review articles will generally be commissioned by the editors and should not be submitted to the journal without explicit invitation. However prospective authors are welcome to send a brief (one to three pages) synopsis, which will be evaluated by the editors.