Computational drug repositioning based on the relationships between substructure-indication
Computational drug repositioning based on the relationships between substructure-indication
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基于子结构与适应症之间关系的计算药物重新定位
DOI：
10.1093/bib/bbaa348
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发表时间：
2021-07-01
影响因子：
9.5
通讯作者：
Chen, Xiujie
中科院分区：
文献类型：
--
作者：
Yang, Jingbo;Zhang, Denan;Chen, Xiujie
目前，药物重新定位的计算方法主要基于药物的整体结构，由于药物局部结构的相似性，限制了新功能的发现。在这篇文章中，我们首次，结合化学基因组学的特点，（亚结构域）和药物基因组学（结构域-适应症）基于药物-靶标相互作用由药物的亚结构和蛋白质的结构域介导的假设，以确定亚结构-适应症之间的关系，并建立药物-亚结构-适应症网络，仅通过药物的亚结构信息预测测试药物的所有治疗效果。总共获得了83205个具有不同相关性评分的药物-适应症关系。我们使用了三种不同的验证方法来表明该方法的准确性和评分系统的可靠性。我们用我们的方法预测了olaparib的所有适应症，包括已知的抗肿瘤作用和文献证实的未知的抗病毒作用，我们还发现了olaparib对DNA修复的抑制机制，通过其特异性的sub 494（o = C-C：C），因为它参与了细胞凋亡途径的多亚功能的低合成（hsa 04210）通过抑制肌醇1，4，5-三磷酸受体（ITPR）和水解聚（ADP核糖）聚合酶。奎尼丁、胺碘酮、米力农、福辛普利四种药物的心电图均显示抗心律失常作用。与以往的研究侧重于药物的整体结构不同，我们的研究在寻找药物的更多治疗作用以及从局部结构相似性预测药物的所有潜在作用和机制方面具有巨大的潜力。
At present, computational methods for drug repositioning are mainly based on the whole structures of drugs, which limits the discovery of new functions due to the similarities between local structures of drugs. In this article, we, for the first time, integrated the features of chemical-genomics (substructure-domain) and pharmaco-genomics (domain-indication) based on the assumption that drug-target interactions are mediated by the substructures of drugs and the domains of proteins to identify the relationships between substructure-indication and establish a drug-substructure-indication network for predicting all therapeutic effects of tested drugs through only information on the substructures of drugs. In total, 83 205 drug-indication relationships with different correlation scores were obtained. We used three different verification methods to indicate the accuracy of the method and the reliability of the scoring system. We predicted all indications of olaparib using our method, including the known antitumor effect and unknown antiviral effect verified by literature, and we also discovered the inhibitory mechanism of olaparib toward DNA repair through its specific sub494 (o = C-C: C), as it participates in the low synthesis of the poly subfunction of the apoptosis pathway (hsa04210) by inhibiting the Inositol 1,4,5-trisphosphate receptor(s) (ITPRs) and hydrolyzing poly (ADP ribose) polymerases. ElectroCardioGrams of four drugs (quinidine, amiodarone, milrinone and fosinopril) demonstrated the effect of anti-arrhythmia. Unlike previous studies focusing on the overall structures of drugs, our research has great potential in the search for more therapeutic effects of drugs and in predicting all potential effects and mechanisms of a drug from the local structural similarity.