College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
College of Chemistry and Materials Science, Fujian Normal University, Fuzhou 350007, China.
Molecules. 2018 Jun 4;23(6):1349. doi: 10.3390/molecules23061349.
Activating Liver X receptors (LXRs) represents a promising therapeutic option for dyslipidemia. However, activating LXRα may cause undesired lipogenic effects. Discovery of highly LXRβ-selective agonists without LXRα activation were indispensable for dyslipidemia. In this study, in silico approaches were applied to develop highly potent LXRβ-selective agonists based on a series of newly reported 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione-based LXRα/β dual agonists. Initially, Kohonen and stepwise multiple linear regression SW-MLR were performed to construct models for LXRβ agonists and LXRα agonists based on the structural characteristics of LXRα/β dual agonists, respectively. The obtained LXRβ agonist model gave a good predictive ability (R² = 0.837, R² = 0.843, Q² = 0.715), and the LXRα agonist model produced even better predictive ability (R² = 0.968, R² = 0.914, Q² = 0.895). Also, the two QSAR models were independent and can well distinguish LXRβ and LXRα activity. Then, compounds in the ZINC database met the lower limit of structural similarity of 0.7, compared to the 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione scaffold subjected to our QSAR models, which resulted in the discovery of ZINC55084484 with an LXRβ prediction value of pEC equal to 7.343 and LXRα prediction value of pEC equal to -1.901. Consequently, nine newly designed compounds were proposed as highly LXRβ-selective agonists based on ZINC55084484 and molecular docking, of which LXRβ prediction values almost exceeded 8 and LXRα prediction values were below 0.
激活肝 X 受体 (LXRs) 是治疗血脂异常的一种很有前途的治疗选择。然而，激活 LXRα 可能会导致不良的生脂作用。因此，发现对 LXRβ 具有高选择性且不激活 LXRα 的激动剂对于治疗血脂异常是必不可少的。在这项研究中，应用计算机模拟方法，基于一系列新报道的 3-(4-(2-丙基苯氧基)丁基)咪唑烷-2,4-二酮基 LXRα/β 双重激动剂，开发了对 LXRβ 具有高选择性的激动剂。首先，分别基于 LXRα/β 双重激动剂的结构特征，使用 Kohonen 和逐步多元线性回归 SW-MLR 构建了 LXRβ 激动剂和 LXRα 激动剂的模型。获得的 LXRβ 激动剂模型具有良好的预测能力(R² = 0.837，R² = 0.843，Q² = 0.715)，而 LXRα 激动剂模型的预测能力甚至更好(R² = 0.968，R² = 0.914，Q² = 0.895)。此外，这两个 QSAR 模型是独立的，可以很好地区分 LXRβ 和 LXRα 活性。然后，在 ZINC 数据库中，与我们的 QSAR 模型中 3-(4-(2-丙基苯氧基)丁基)咪唑烷-2,4-二酮骨架相比，符合结构相似性下限 0.7 的化合物，结果发现 ZINC55084484 化合物具有 LXRβ 预测值 pEC 等于 7.343 和 LXRα 预测值 pEC 等于-1.901。因此，基于 ZINC55084484 和分子对接，提出了 9 种新设计的化合物作为对 LXRβ 具有高选择性的激动剂，其中 LXRβ 的预测值几乎超过 8，而 LXRα 的预测值低于 0。
