Identifying selective agonists targeting LXRβ from terpene compounds of alismatis rhizoma

Hyperlipidemia is thought of as an important contributor to coronary disease, diabetes, and fatty liver. Liver X receptor β (LXRβ) was considered as a validated target for hyperlipidemia therapy due to its role in regulating cholesterol homeostasis and immunity. However, many current drugs applied in clinics are not selectively targeting LXRβ, and they can also activate LXRα which activates SREBP-1c that worked as an activator of lipogenic genes. Therefore, exploiting agonists selectively targeting LXRβ is urgent. Here, computational tools were used to screen potential agonists selectively targeting LXRβ from 112 terpenes of alismatis rhizoma. Firstly, a structural analysis between selective and nonselective agonists was used to explore key residues of selective binding with LXRβ. Our data indicated that Phe²⁷¹, Ser²⁷⁸, Met³¹², His⁴³⁵, and Trp⁴⁵⁷ were important to compounds binding with LXRβ, suggesting that engaging ligand interaction with these residues may provide directions for the development of ligands with improved selective profiles. Then, ADMET analysis, molecular docking, MD simulations, and calculation of binding free energy and its decomposition were executed to screen the agonists whose bioactivity was favorable from 112 terpenes of alismatis rhizoma. We found that two triterpenes 16-hydroxy-alisol B 23-acetate and alisol M 23-acetate showed favorable ADMET properties and high binding affinity against LXRβ. These compounds could be considered as promising selective agonists targeting LXRβ. Our work provides an alternative strategy for screening agonists selectively targeting LXRβ from alismatis rhizoma for hyperlipidemia disease treatment.