Identfication of Potent LXRβ-Selective Agonists without LXRα Activation by In Silico Approaches

Abstract

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.

Review of in silico studies dedicated to the nuclear receptor family: Therapeutic prospects and toxicological concerns

“…within a defined descriptors similarity threshold with their nearest neighbors of the training set ( 45 ). In order to enhance the chemical space for which prediction can be made, QSAR models can be combined with other ones with complementary ADs or with a SB model such as docking ( 67 , 68 , 74 , 81 ).…”

“…LXR presents two isoforms (LXRα and LXRβ) that are both ubiquitously expressed ( 65 , 67 , 130 – 132 ). LXR serves primarily as a reverse cholesterol transporter within the lipid metabolism, protecting cells from cholesterol excess ( 66 , 67 ) and is involved in many physiological processes. Thus, LXR represents a promising therapeutic target for cardiovascular diseases, dyslipidemia and cancer treatment ( 66 ).…”

“…Thus, LXR represents a promising therapeutic target for cardiovascular diseases, dyslipidemia and cancer treatment ( 66 ). However, it has been shown that LXRα activation can lead to undesired lipogenic effects like increased hepatic lipogenesis or liver steatosis whereas LXRβ activation does not and can even reduce them ( 67 ). Designing LXRβ selective compounds to treat dyslipidemia appears as a promising strategy yet difficult to achieve due to the high similarity between both isoforms LBD.…”

“…In the first article, Chen et al. ( 67 ) built a selective LB model using an association of Kohonen maps and stepwise multiple regression. The model relied on the structures of newly reported dual agonists and was associated with R 2 equal to 0.837 and 0.843 for train and test set respectively.…”

Microwave-Promoted Total Synthesis of Puniceloid D for Modulating the Liver X Receptor

“…An essential role for liver X receptors is to regulate innate immunity, inflammatory responses, and lipid and cholesterol metabolism [ 9 , 10 , 11 ]. There are two isoforms of the liver X receptor: LXRα and LXRβ [ 12 ]. While LXRβ (NR1H2) is expressed everywhere, LXRα (NR1H3) is expressed in metabolically active tissues such as the liver, adipose, kidney, macrophages, and intestines [ 13 , 14 ].…”