【摘要】 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射线衍射测得的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的选择抑制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R2 =0 .71,标准偏差S =0 .47,F( 1.14) =3 4 .74更多还原

【Abstract】 One of approaches to reducing NSAIDs (nonsteroidal antiinflammatory dru gs)-associated gastrointestinal adverse is to convert NSAIDs into selective CO X-2 inhibitors by structural modifications. However recent observations indicat e that the expression of COX-2 appears to be required for ovulation and fertili zation. This implicates that the optimal compromise between the beneficial and t he deleterious effects of selective COX-2 inhibitors should be made for the treatm e nt 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 app li cation of DOCK 4.0 program and minimization method. The significant correlation between compound selectivity (COX-2 vs COX-1) and the difference of docking e ne rgy [ΔE (COX-2) -ΔE (COX-1) ] 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 ef fectively improved. Expansion of the approach may be envisioned for the modific ation of other COX inhibitors containing phenyl ring binding at this pocket.更多还原