Identifying of selective agonists targeting LXRβ from terpene compounds of Alismatis Rhizoma

Hyperlipidemia is thought as an important contributor to coronary disease, diabetes and fatty liver. Liver X receptors 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 clinic are not selectively targeting LXRβ and they can also activate LXRα which activate SREBP-1c worked as activator of lipogenic genes. Therefore, exploiting agonists selectively targeting LXRβ are urgent. Here, computational tools were used to screen potential agonists selectively targeting LXRβ from 112 terpenes of Alismatis Rhizoma. Firstly, structural analysis between selective and nonselective agonists were used to explore key residues of selective binding with LXRβ. Our data indicated that Phe271, Ser278, Met312, His435, Trp457 were important to compounds binding with LXRβ, suggesting that engaging ligand interaction with these residues may provide directions for 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 were 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.