Lopez de Compadre R L, Pearlstein R A, Hopfinger A J, Seydel J K
J Med Chem. 1987 May;30(5):900-6. doi: 10.1021/jm00388a026.
A set of 36 congeneric 4-aminodiphenyl sulfones with measured inhibition potencies of dihydropteroate synthase were studied by using both linear free energy and molecular modeling methods. The goals of the investigation were to identify the "active" conformation for these compounds as inhibitors and, correspondingly, to contruct a quantitative structure-activity relationship (QSAR). These molecules are quite flexible and possess multiple conformational energy minima. Application of molecular shape analysis (MSA), using all intramolecular energy minima as part of the analysis, was not successful in generating a QSAR. However, the calculated intramolecular conformational entropy of these compounds was found to correlate with inhibition potency leading to a highly significant QSAR. Inhibition potency increases as entropy decreases. A decrease in entropy enhances the population of specific, symmetry-related minimum-energy conformations. In this indirect way, it was possible to postulate an "active" conformation. This investigation illustrates that specific knowledge of the "active" shape of a molecule may not provide the information needed to quantitatively explain the observed structure-activity relationship.
利用线性自由能和分子建模方法，对一组36种具有测量二氢蝶酸合酶抑制活性的同类4-氨基二苯砜进行了研究。该研究的目的是确定这些化合物作为抑制剂的“活性”构象，并相应地构建定量构效关系（QSAR）。这些分子具有相当的灵活性，并拥有多个构象能量最小值。使用所有分子内能量最小值作为分析的一部分，分子形状分析（MSA）在生成QSAR方面并不成功。然而，发现这些化合物的计算分子内构象熵与抑制活性相关，从而产生了高度显著的QSAR。抑制活性随着熵的降低而增加。熵的降低增加了特定的、对称相关的最低能量构象的数量。通过这种间接方式，可以推测出“活性”构象。这项研究表明，分子“活性”形状的特定知识可能无法提供定量解释观察到的构效关系所需的信息。
