Hopfinger A J
J Med Chem. 1981 Jul;24(7):818-22. doi: 10.1021/jm00139a010.
A quantitative structure-activity relationship (QSAR) investigation of a set of 23 substituted 2,4-diamino-5-benzylpyrimidines spanning an activity range of 1.8 log (1/C) units was carried out using molecular shape analysis (MSA). C is the molar concentration necessary for 50% inhibition of bovine liver dihydrofolate reductase (DHFR). The "active" shape of these compounds was deduced by comparing the change in conformational state to the activity of four compounds outside the data base described above. A correlation equation, and analogous in descriptor form to those developed earlier for DHFR inhibition by substituted, 2,4-diaminotriazines and -quinazolines, was constructed. The correlations coefficient, r, was 0.931 and the standard deviation of fit, s, was 0.137. The results suggest that these pyrimidines bind to DHFR with shape features different from both the triazines and quinazolines. It is postulated from the "active" shape of the pyrimidines that it is preferable to substitute at the meta position of the benzyl ring rather than at the para position.
使用分子形状分析（MSA）对一组23种取代的2,4 - 二氨基 - 5 - 苄基嘧啶进行了定量构效关系（QSAR）研究，这些化合物的活性范围为1.8 log(1/C) 单位。C是抑制牛肝二氢叶酸还原酶（DHFR）50%所需的摩尔浓度。通过比较构象状态的变化与上述数据库之外的四种化合物的活性，推断出这些化合物的“活性”形状。构建了一个相关方程，其描述符形式类似于早期针对取代的2,4 - 二氨基三嗪和 - 喹唑啉对DHFR抑制作用所建立的方程。相关系数r为0.931，拟合标准偏差s为0.137。结果表明，这些嘧啶与DHFR结合的形状特征不同于三嗪和喹唑啉。从嘧啶的“活性”形状推测，苄基环的间位取代比对位取代更合适。
