Identification of Novel Compounds Targeting the Liver X Receptor (LXR): In-silico Studies, Screening, Molecular Docking, and Chemico-pharmacokinetic Analysis

Studies have demonstrated the association between LXR activity dysregulation with many diseases, including atherosclerosis, diabetes and cancer. In recent years, several LXR agonists have surfaced, but none have been approved for human use due to adverse effects or unforeseen reasons. In this study, we first analysed the mRNA and protein expression of LXRs across tissues, network and pathway analysis, and reinterpreted their physiological function and disease association by utilizing multiple biological data repositories, including RNA-seq human protein atlas, DisGeNET, etc. Then, we performed ligand-based virtual screening, chemico-pharmacokinetic analysis, docking and simulation to identify potential new compounds. Our findings of mRNA, protein expression, network and disease enrichment analysis reveal diverse physiological functions of LXRs addressing the possibility of pharmacological manipulation with small molecules would provide therapeutic strategies for disease management. Evaluation of the docking and chemico-pharmacokinetic properties directed to the selection of LXR-623 and AZ876 as promising candidates for LXR-α and LXR-β for further in-silico investigation. Comprehensive screening for new ligands targeting LXRs based on the chemical structures of LXR-623 and AZ876, identified ZINC000005399501 and ZINC000021912941 with the highest binding affinity (−9.8 and −10.7 kcal/mol) for LXRα and LXRβ, respectively. Our results also supported in simulation study, along with favorable chemico-pharmacokinetic features.