A QSAR INVESTIGATION OF DIHYDROFOLATE-REDUCTASE INHIBITION BY BAKER TRIAZINES BASED UPON MOLECULAR SHAPE-ANALYSIS
A QSAR INVESTIGATION OF DIHYDROFOLATE-REDUCTASE INHIBITION BY BAKER TRIAZINES BASED UPON MOLECULAR SHAPE-ANALYSIS
复制标题
DOI：
10.1021/ja00544a005
复制
发表时间：
1980-01-01
影响因子：
15
通讯作者：
HOPFINGER, AJ
中科院分区：
文献类型：
--
作者：
HOPFINGER, AJ
分子形状描述符（三维）定义了一组贝克三嗪，这是二氢叶酸还原酶（DHFR）抑制剂。两个形状描述符，和1个物理化学特征，3-和4-取代基辛醇/水片段常数的总和，需要解释在数据库中的5.11 log（1/C）单位的活性范围。C是50%体外抑制的三嗪的摩尔浓度。分子形状描述符SO与分子对之间的公共重叠空间体积成比例。另一个形状描述符D4是三嗪分子中4-取代基长度的量度。该化合物数据库由27种化合物组成，这些化合物被选择来代表Baker三嗪组内的化合物的每个可能的构象类别。数据库中没有化合物必须作为异常物排除。在这项研究中产生的定量构效关系（QSAR）进行了测试，在7个已知的化合物，并用于预测5个活性化合物。这项研究构成，也许是迄今为止最清楚的实例，其中考虑分子形状/构象导致药物效力的定量描述得到改善。
Molecular shape descriptors (3-dimensional) were defined for a set of Baker triazines which are dihydrofolate reductase (DHFR) inhibitors. Two shape descriptors, and 1 physicochemical feature, the sum of the 3- and 4-substituent octanol/water fragment constants, are needed to explain a range in activity in the data base of 5.11 log (1/C) units. C is the molar concentration of triazine for 50% in vitro inhibition. A molecular shape descriptors, SO, is proportional to the common overlap steric volume between pairs of molecules. The other shape descriptor, D4, is a measure of the length of the 4-substituent in a triazine molecule. The compound data base consists of 27 compounds selected to represent each possible conformational class of compounds within the set of Baker triazines. No compound in the data base had to be eliminated as an outlyer. The quantitative structure-activity relationships (QSAR) generated in this study are tested on 7 known compounds and used to predict 5 active compounds. This study constitutes, perhaps, the clearest instance to date where the consideration of molecular shape/conformation leads to an improved quantitative description of drug potencies.