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

作　　者：赵东升 万金玉 高银谊 郭幼红 Zhao Dongsheng;Wan Jinyu;Gao Yinyi;Guo Youhong(College of Pharmacy,Quanzhou Medical College,Quanzhou,362100;Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou,510080)

机构地区：[1]泉州医学高等专科学校药学院,泉州362100 [2]中山大学中山医学院,广州510080

出　　处：《化学通报》2020年第10期940-945,共6页Chemistry

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。Phosphodiesterase 4 b 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 4 b(PDE4 b)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(3 D-QSAR)model for a series of pyrimidine derivatives PDE4 b inhibitors.The molecular docking method was used to study the interactions between inhibitors and PDE4 b.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 PDE4 b inhibitors.

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 

分 类 号：TQ464.8[化学工程—制药化工]