磷酸二酯酶4b抑制剂定量构效关系及分子对接研究

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。

Quantitative Structure-Activity Relationship and Molecular Docking of Phosphodiesterase 4b Inhibitors

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.