Berellini Giuliano, Cruciani Gabriele, Mannhold Raimund
Laboratory for Chemometrics and Cheminformatics, Department of Chemistry, University of Perugia, Via Elce di sotto 10, I-06123 Perugia, Italy.
J Med Chem. 2005 Jun 30;48(13):4389-99. doi: 10.1021/jm049024x.
About 20 non-peptide angiotensin II receptor antagonists are in various stages of clinical development. Different modeling approaches were used to predict the pharmacophoric requirements for AT(1) (angiotensin II receptor subtype 1) affinity. However, to our knowledge, none was used to predict both the selectivity toward AT(1) and AT(2) (angiotensin II receptor subtype 2) receptor subtypes. In this paper, partial least squares discriminant analysis is applied to derive the chemical features guiding AT(1) and AT(2) selectivity or mixed AT(1)/AT(2) receptor binding. The method can be used to modulate AT(1) versus AT(2) selectivity. Concerns that unopposed stimulation of the AT(2) receptor might produce adverse effects initiated a search for new balanced antagonists. Moreover, it can serve as a fast filtering procedure in database searches. Finally, some relevant pharmacokinetics and metabolic properties of the database of 53 compounds are calculated using the VolSurf and MetaSite software to allow the simultaneous characterization of pharmacodynamic and pharmacokinetics properties of the chemical space of angiotensin II receptor antagonists.
约20种非肽类血管紧张素II受体拮抗剂正处于临床开发的不同阶段。人们采用了不同的建模方法来预测对AT(1)（血管紧张素II 1型受体亚型）亲和力的药效团要求。然而，据我们所知，尚无方法用于预测对AT(1)和AT(2)（血管紧张素II 2型受体亚型）受体亚型的选择性。本文应用偏最小二乘判别分析来推导指导AT(1)和AT(2)选择性或混合AT(1)/AT(2)受体结合的化学特征。该方法可用于调节AT(1)与AT(2)的选择性。由于担心对AT(2)受体的无对抗刺激可能产生不良反应，人们开始寻找新型平衡拮抗剂。此外，它可作为数据库搜索中的快速筛选程序。最后，使用VolSurf和MetaSite软件计算了53种化合物数据库的一些相关药代动力学和代谢特性，以便同时表征血管紧张素II受体拮抗剂化学空间的药效学和药代动力学特性。
