选择性磷酸二酯酶4D(PDE4D)抑制剂的计算模型建立

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.

Establishment of a computational model for selective phosphodiesterase 4D (PDE4D) allosteric inhibitor

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.