Demyttenaere-Kovatcheva Assia, Cronin Mark T D, Benfenati Emilio, Roncaglioni Alessandra, Lopiparo Elena
School of Pharmacy and Chemistry, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, England.
J Med Chem. 2005 Dec 1;48(24):7628-36. doi: 10.1021/jm050604j.
Three-dimensional (3D) quantitative structure-activity relationship (QSAR) and structure-activity relationship (SAR) analyses were applied concurrently to a data set of highly selective estrogen receptor beta (ERbeta) agonists. The data set consisted of diphenolic azoles characterized by similar structural skeletons but with different binding modes to the estrogen receptor site. Models were developed separately with respect to the relative binding affinities (RBAs) to ERalpha and ERbeta. Steric and electrostatic fields were calculated for a training set of 72 compounds using comparative molecular field analysis (CoMFA). The model developed for ERalpha RBA yielded R2 of 0.91 and q(cv)2 of 0.60. The model developed for ERbeta RBA yielded R2 of 0.95 and q(cv)2 of 0.40. Both models were validated successfully using an external test set of 32 compounds. A new concept of test set evaluation based on the variability of the biological response due to the variability of the living organism has been introduced. The CoMFA analysis was supported by a SAR study. In addition to the most favorable steric and electrostatic regions identified by CoMFA, a number of structural descriptors were identified as being important for binding. These are the number of substituents attached to the main skeleton of each compound, the largest distance between the oxygen atoms of each molecule, and the angle defined by the planes that split the phenyl or the naphthyl and the benzisoxazole or the benzoxazole moiety in a morphometrically longitudinal way.
三维（3D）定量构效关系（QSAR）和构效关系（SAR）分析同时应用于一组高选择性雌激素受体β（ERβ）激动剂的数据。该数据集由二酚唑类化合物组成，其结构骨架相似，但与雌激素受体位点的结合模式不同。针对与ERα和ERβ的相对结合亲和力（RBA）分别建立了模型。使用比较分子场分析（CoMFA）对72种化合物的训练集计算了空间和静电场。为ERα RBA建立的模型R2为0.91，q（cv）2为0.60。为ERβ RBA建立的模型R2为0.95，q（cv）2为0.40。两个模型均使用32种化合物的外部测试集成功验证。引入了基于生物体变异性导致的生物反应变异性的测试集评估新概念。CoMFA分析得到了SAR研究的支持。除了CoMFA确定的最有利的空间和静电区域外，还确定了一些对结合很重要的结构描述符。这些是连接到每种化合物主骨架上的取代基数量、每个分子中氧原子之间的最大距离，以及以形态计量纵向方式分割苯基或萘基与苯并异恶唑或苯并恶唑部分的平面所定义的角度。
