In silico identification of small molecules as novel LXR agonists for the treatment of cardiovascular disease and cancer.

Liver X receptor (LXR), a member of the nuclear receptor superfamily, mainly serves as a reverse cholesterol transporter in lipid metabolism. It has been demonstrated that LXR is a promising target for the treatment of cardiovascular diseases. LXR is also involved in cancer metabolism, glucose homeostasis, immunity, and various physiological processes. The antitumor function of LXR has become of great interest to researchers in recent years. However, while it is believed that activating LXR with small molecules could be a promising approach to cancer treatment, effective drugs that target LXR are yet to be reported. To find compounds that are potentially capable of activating LXR, we utilized a high-throughput screening method to search the MolMall database for suitable compounds. Seven candidates with lower GB/SA Hawkins scores than the reference ligand T0901317 were identified. Based on the results of molecular dynamics (MD) simulations, binding free energy analysis, and an analysis of the agonism mechanism, ZINC90512020 and ZINC3845032 were predicted to have high affinities for LXR and high relative stabilization, and were therefore selected as potential LXR agonists. Both of these compounds will undergo further development with a view to utilizing them for the treatment of LXR-related cardiovascular diseases or cancers.