摘要
选择26个基于吡啶和嘧啶环的选择性磷酸二酯酶4D(PDE4D)抑制剂,通过软件SYBYL-X2.1.1中的CoMFA,CoMSIA,Surflex-dock及GALAHAD模块研究其构效关系与分子对接模式.所得CoMFA建模的q^2和r^2分别为0.54与0.996,CoMSIA建模的q^2和r^2分别为0.536与0.942,表明2个模型均具有较高预测能力.分子对接结果表明,ASP367与GLN535可能是配体分子与PDE4D蛋白作用的关键氨基酸残基.药效团结果表明,芳香杂环的母核结构以及侧链具有多个氢键供体或受体取代基的结构对化合物的活性贡献较大.该研究结果为设计合成更多具有选择性的PDE4D抑制剂提供理论指导.
Twenty-six pyridine-and pyrimidine-based selective PDE4 D allosteric inhibitors were selected, and the CoMFA, CoMSIA, Surflex-dock and GALAHAD, in software SYBYL-X2.1.1 were used to study the structure-activity relationship and molecular docking mode. The optimal CoMFA model exhibited good cross-validated q^2 and conventional r^2 values at 0.54 and 0.996, and the CoMSIA modeled q^2 and r^2 were 0.536 and 0.942. This result confirmed the high predictive capacity of the resultant CoMFA and CoMSIA models. The molecular docking analysis showed that ASP367 and GLN535 may be key amino acid residues for the interaction of ligand molecules with PDE4 D protein. The pharmacophore results indicated that aromatic heterocyclic core structure and the structure of the side chain have hydrogen bond donor or acceptor substituent contribute significantly to the activity of the compounds. The results provide a foundation for the future design and synthesis of more selective phosphodiesterase 4 D(PDE4 D) inhibitors.
作者
刘景陶
曹玉成
王恺奕
LIU Jing-tao;CAO Yu-cheng;WANG Kai-yi(Department of Science,Hetao College,Bayan Nur 015000,China;School of Pharmacy,Yantai University,Yantai 264005,China)
出处
《分子科学学报》
CAS
北大核心
2020年第3期249-256,共8页
Journal of Molecular Science
基金
内蒙古自治区高等学校科学研究项目(NJZY19245)。
关键词
吡啶与嘧啶类
磷酸二酯酶4D
三维定量构效关系
分子对接
药效团
pyridine and pyrimidine
phosphodiesterase 4D
three-dimensional quantitative structure-activity relationship
molecular docking
pharmacophore
