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 (R²train = 0.837, R²test = 0.843, Q²LOO = 0.715), and the LXRα agonist model produced even better predictive ability (R²train = 0.968, R²test = 0.914, Q²LOO = 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 pEC50 equal to 7.343 and LXRα prediction value of pEC50 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.
Keywords: Kohonen; LXRβ-selective agonists; QSAR modeling; molecular docking.