COX抑制剂——氟比洛芬衍生物的作用方式及选择性研究  

Study on Molecular Mechanism and COX-2 Selectivity of Flurbiprofen Derivative s

作　　者：郭长彬[1] 易翔[1] 徐志斌[1] 郭宗儒[1] 

机构地区：[1]中国医学科学院中国协和医科大学药物研究所,北京100050

出　　处：《化学学报》2003年第10期1653-1657,共5页Acta Chimica Sinica

基　　金：国家自然科学基金 (No .2 0 0 72 0 57)资助项目

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 .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 [DeltaE((COX-2)) - DeltaE((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 effectively improved. Expansion of the approach may be envisioned for the modification of other COX inhibitors containing phenyl ring binding at this pocket.

关 键 词：COX抑制剂 氟比洛芬衍生物 作用方式 选择性 环氧合酶 分子对接 Cscore评分 

分 类 号：R914[医药卫生—药物化学]