| 赵东升,万金玉,高银谊,郭幼红.化学通报,2020,83(10):940-945. |
| 磷酸二酯酶4b抑制剂定量构效关系及分子对接研究 |
| Quantitative Structure-Activity Relationship and Molecular Docking of Phosphodiesterase 4b Inhibitors |
| 投稿时间：2020-03-13 修订日期：2020-06-12 |
| DOI： |
| 中文关键词: 磷酸二酯酶4b(PDE4b) 抑制剂 三维定量构效关系 比较分子场 分子对接 |
| 英文关键词:Phosphodiesterase 4b (PDE4b) Inhibitors 3D-QSAR CoMFA Molecular docking |
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| 中文摘要: |
| 磷酸二酯酶4（PDE4）是第二信使环磷酸腺苷（cAMP）选择性高亲和力的水解酶，影响气道平滑肌、炎性细胞和免疫细胞的功能，选择性PDE4b抑制剂作为抗炎药治疗哮喘和慢性阻塞性肺病（COPD）因为不会引起恶心呕吐等副反应而受到极大的关注。本文使用比较分子场（CoMFA）方法，对系列嘧啶二芳基取代的PDE4b抑制剂构建了合理的三维定量构效关系（3D-QSAR）模型，使用分子对接方法研究了抑制剂与酶的相互作用，发现该系列化合物的嘧啶环2位引入带有较大电负性基团取代的五元环状烃基可提升活性；嘧啶环4位、5位两个碳原子上建议保留小体积取代基；嘧啶环6位引入带有氢键给体或氢键受体取代的芳烃基可增加化合物活性。本研究可为后续合理设计高效的PDE4b抑制剂提供理论指导。 |
| 英文摘要: |
| Phosphodiesterase 4b plays a key role in catalyzing the hydrolysis of the secondary signal messenger cyclic adenosine monophosphate (cAMP), which is able to regulate the function of airway smooth muscle, inflammatory cells and immune cells. Selective phosphodiesterase 4b (PDE4b) inhibitors received great attentions because they do not cause nausea and vomit while being used as anti-inflammatory drugs for asthma and chronic obstructive pulmonary disease (COPD). In this paper, a comparative molecular field (CoMFA) method was used to construct a reasonable three-dimensional quantitative structure-activity relationship (3D-QSAR) model for a series of pyrimidine derivatives PDE4b inhibitors. The molecular docking method was used to study the interactions between inhibitors and PDE4b. The results showed that the introduction of a five-membered cyclic hydrocarbon group with an electronegative group at the 2 position of the pyrimidine can increase the activity. Small substituent group at the 4 and 5 positions of the pyrimidine ring is suitable. The introduction of an aromatic hydrocarbon group with a hydrogen bond donor or hydrogen bond acceptor at the 6-position of pyrimidine helps to improve the activity of the compounds. This study provides theoretical guidance for the rational design of efficient PDE4b inhibitors. |
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