苯并环庚并吡啶类法呢基蛋白转移酶抑制剂的三维定量构效关系的研究

目的建立苯并环庚并吡啶类法呢基蛋白转移酶(FPTase)抑制剂三维定量构效关系模型。方法和结果 利用比较分子力场分析方法对69个苯并环庚并吡啶类FPTase抑制剂建立了三维定量构效模型,模型的交叉验证系数R²=0.581,非交叉验证系数R²=0.968,SE=0.148,F=198.7。结论利用所获得CoMFA模型对10个FPTase抑制剂进行了活性预测,预测值与实测值相近,说明利用该模型进行新苯并环庚并吡啶类FPTase抑制剂分子设计有较好的可信度。

THREE DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF A SERIES OF BENZOCYLOHEPTAPYRIDINE FARNESYLTRANSFERASE INHIBITORS

AIM: To build a three dimensional structure model that correlates the biological activities and the structures of a series of 1-(8-chloro-6,11-dihydro-5H-benzo5,6]cyclohepta-1,2-]pyridin-11-yl) piperazines farnesyl protein transferase (FPTase) inhibitors. METHODS AND RESULTS: Mutation in the ras oncogene takes place in many human cancers, involving 30%-50% of colon and 90% of pancreatic cancer. Ras proteins function as central switches for signals given by growth factors that direct cell growth and cell differentiation. The dependence of the transforming activity of Ras on the farnesylation has led to intense search for FPTase inhibitors that may have therapeutic pontetial as anticancer agents. This paper is to build a three dimensional structural model that correlates the biological activities and the structures of a series of FPTase inhibitors. The investigated sixty-nine inhibitors contain six types of structures, the optimal conformations of which were studied using system search. A three dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed using the method of comparative molecular field analysis (CoMFA). The resulting cross-validation R2 is 0.581, non-cross-validation R2 0.968, SE 0.148, F 198.7. The predicted activities of 10 inhibitors using this 3D-QSAR model are comparable to the experimental activities, indicating that the 3D-QSAR model has ability to predict activities of new inhibitors and offers an approach to design new FPTase inhibitors. CONCLUSION: The information of CoMFA model offers an approach to designing new FPTase inhibitors.