2-苯基4-吡喃酮类COX-2抑制剂的三维构效关系研究

 环氧化酶（cyclooxygenase，COX）家族是非甾体类抗炎药物的作用靶酶，其中COX-2是 NSAIDs药物发挥作用与治疗炎症有关的靶点。使用三维定量构效关系研究方法研究2-苯基4-吡喃酮类COX-2抑制剂的分子结构与生物活性之间的定量关系，并构建三维定量构效关系模型。CoMSIA模型证实该类化合物的结构参数和其抑制活性存在明显的相关性（R²为0.929），且有较好预测能力（q²为0.746）；同时使用“留五法”证实模型的稳定和可靠。三维构效关系模型系数等势图显示Subset A和B的R取代基4位上官能团变化对活性影响最大，在结构修饰时需要优先考虑；Subset A的R取代基2位上官能团的影响次之。

Studies on 3D Quantitative Structure-Activity Relationships-of 2(4-Methanesulfonylphenyl) pyran-4-ones as Selective COX-2 Inhibitors

Cycloxygenase (COX) is an enzyme that exits in two isoforms, constitutive COX-1 and inducible COX-2 The former is considered to be a “housekeeping” enzyme whereas the latter is induced in pathological condition. With inhibition of COX-2, non steroidal anti-inflammatory drugs (NSAIDs) exhibit their antipyretic, analgesic, anti inflammatory therapeutic actions. In order to elucidate the relationships between structural character and biological activity of title compounds, 3D quantitative structure-activity relationships (3D-QSAR) methods were performed based on the comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) approaches. In this research, a favorable CoMSIA model achieving a satisfied q² value (q² = 0.746 and R² = 0.929) was derived with the combination of steric and electrostatic fields. Contour maps of the model revealed that important structural attributes should be firstly considered taking place in position 4 of R substitute in both subset A and B while position 2 in subset A in the second place.