COX抑制剂——氟比洛芬衍生物的作用方式及选择性研究

用DOCK4.0程序搜索氟比洛芬衍生物与环氧合酶结合的构象。用Cscore综合评 分体系确定最佳构象，复合物经分子力学优化后，发现衍生物在COX-1中的取向和 位置与X射线衍射测犁晶体复合物中氟比洛芬作用方式相同；衍生物在COX-2中也有 与氟比洛芬类似的结合方式。衍生物对COX-2/COX-1 的选择掏性与衍生物作用于两 种酶的结合自由能之差有较好的相关性。相关系数

Study on Molecular Mechanism and COX-2 Selectivity of flurbiprofen Derivatives

One of approaches to reducing NSAIDs (nonsteroidal antiinflammatory drugs)-associated gastrointestinal adverse is to convert NSAIDs into selective COX-2 inhibitors by structural modifications. However recent observations indicate that the expression of COX-2 appears to be required for ovulation and fertilization. This implicates that the optimal compromise between the beneficial and the deleterious effects of selective COX-2 inhibitors should be made for the treatment of inflammation. In the present paper the molecular mechanism of a series of Flurbiprofen derivatives targeting towards COX-1 and COX-2 was explored by application of DOCK 4.0 program and minimization method. The significant correlation between compound selectivity ( COX-2 vs COX-1) and the difference of docking energy [ΔE_(cox-2) - ΔE_(cox-i)] provides some insights into that the substituents in the distal phenyl ring have no positive effect on the binding to both COX-1 and COX-2 compared with Flurbiprofen. However, the COX-2 selectivity has been effectively improved. Expansion of the approach may be envisioned for the modification of other COX inhibitors containing phenyl ring binding at this pocket.