一类双氯芬酸类似物环氧合酶抑制剂作用模式的理论研究

Theoretical research on the interaction modes of diclofenac analogues as COX-2 inhibitors

基于1PXX晶体结构以及以晶体中双氯芬酸D IF701为模版的双氯芬酸类似物2型环氧合酶(COX-2)抑制剂的结构,利用药效团和自组织分子力场分析方法,探讨了COX-2与抑制剂的相互作用模式。建立了双氯芬酸药效团模型和COX-2抑制剂三维定量构效关系模型,并且两种方法所得的模型吻合;确定的COX-2与抑制剂的作用模式,可以指导抑制剂的设计,用于开发抗炎药物。

Diclofenac analogues are important medicines belonging to the pharmaceutical family known as non-steroidal anti-inflammatory drugs （NSAIDs）. Theoretical research on the interactions between COX-2 and dielofenac analogues as inhibitors has been carried out in order to identify new potent inhibitors. The pharmacophore model of diclofenac was generated based on a ligand-macromolecule complex interpretation from pdb 1PXX. We aligned the optimized structures of the diclofenac analogues onto a template structure and 36 diclofenac analogues were investigated with the aim of developing a 3D-QSAR model using self-organizing molecular field analysis （SOMFA）. The interactions between COX-2 and diclofenac analogues as inhibitor were illustrated clearly, and the pharmaeophore models and 3D-QSAR model were fitted very well by the data. The results obtained in this work will be useful for designing new active inhibitors.