Marot C, Chavatte P, Morin-Allory L, Viaud M C, Guillaumet G, Renard P, Lesieur D, Michel A
Institut de Chimie Organique et Analytique, associé au CNRS, Université d'Orléans, BP 6759, 45067 Orléans Cedex 2, France.
J Med Chem. 1998 Nov 5;41(23):4453-65. doi: 10.1021/jm980026p.
Conformational analysis was used to characterize the agonist pharmacophore for melatonin sheep brain receptor recognition and activation. The molecular geometry shared by all conformations of the selected active ligands was determined. Assuming that all the compounds interact at the same binding site at the receptor level, 2-iodomelatonin pharmacophoric conformation served as a template for the superimposition of 64 structurally heterogeneous agonists constituting the training set used to perform a three-dimensional quantitative structure-activity relationship study via the comparative molecular field analysis method. A statistically significant model was obtained for the totality of the compounds (n = 64, q2 = 0.62, N = 6, r2 = 0.96, s = 0.28, F = 249) with steric, electrostatic, and lipophilic relative contributions of 28%, 35%, and 37%, respectively. The predictive power of the proposed model was discerned by successfully testing the 78 agonist ligands constituting the test set. The model so obtained and validated brings important structural insights to aid the design of novel melatoninergic agonist ligands prior to their synthesis.
构象分析用于表征褪黑素绵羊脑受体识别和激活的激动剂药效团。确定了所选活性配体所有构象共有的分子几何结构。假设所有化合物在受体水平的同一结合位点相互作用，2-碘褪黑素的药效团构象用作叠加64种结构异质激动剂的模板，这些激动剂构成了用于通过比较分子场分析方法进行三维定量构效关系研究的训练集。对于所有化合物（n = 64，q2 = 0.62，N = 6，r2 = 0.96，s = 0.28，F = 249）获得了一个具有统计学意义的模型，其空间、静电和脂溶性相对贡献分别为28%、35%和37%。通过成功测试构成测试集的78种激动剂配体，识别了所提出模型的预测能力。如此获得并验证的模型为新型褪黑素能激动剂配体的合成前设计提供了重要的结构见解。
