Jyrkkärinne Johanna, Windshügel Björn, Rönkkö Toni, Tervo Anu J, Küblbeck Jenni, Lahtela-Kakkonen Maija, Sippl Wolfgang, Poso Antti, Honkakoski Paavo
Departments of Pharmaceutics and Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland.
J Med Chem. 2008 Nov 27;51(22):7181-92. doi: 10.1021/jm800731b.
The human constitutive androstane receptor (CAR, NR1I3) is an important regulator of xenobiotic metabolism and other physiological processes. So far, only few CAR agonists are known and no explicit mechanism has been proposed for their action. Thus, we aimed to generate a 3D QSAR model that could explain the molecular determinants of CAR agonist action. To obtain a sufficient number of agonists that cover a wide range of activity, we applied a virtual screening approach using both structure- and ligand-based methods. We identified 27 novel human CAR agonists on which a 3D QSAR model was generated. The model, complemented by coregulator recruitment and mutagenesis results, suggests a potential activation mechanism for human CAR and may serve to predict potential activation of CAR for compounds emerging from drug development projects or for chemicals undergoing toxicological risk assessment.
人类组成型雄甾烷受体（CAR，NR1I3）是外源性物质代谢及其他生理过程的重要调节因子。到目前为止，已知的CAR激动剂很少，且尚未有人提出其明确的作用机制。因此，我们旨在建立一个三维定量构效关系（3D QSAR）模型，以解释CAR激动剂作用的分子决定因素。为了获得足够数量且活性范围广泛的激动剂，我们应用了基于结构和配体的虚拟筛选方法。我们鉴定出了27种新型人类CAR激动剂，并据此建立了3D QSAR模型。该模型结合共调节因子募集和诱变结果，提示了人类CAR的潜在激活机制，可用于预测药物开发项目中出现的化合物或正在进行毒理学风险评估的化学物质对CAR的潜在激活作用。
