Revisiting the Role of Liver X Receptors (LXRs) in Disease: In-silico Discovery of Novel Modulators Through Molecular Docking and Chemico-Pharmacokinetic Profiling

Liver X Receptors (LXRs) play a critical role in regulating lipid metabolism and inflammation, with their altered activity linked to several metabolic diseases. Although several LXR agonists have been identified, their clinical use has been limited due to adverse effects. In this study, we first leveraged multiple biological data repositories (including RNA-seq, Human Protein Atlas, DisGeNET, and WebGestalt) to examine the expression of LXRs at both the mRNA and protein levels across various tissues. We performed network and pathway analyses to redefine the physiological roles and disease associations of LXRs. Our findings emphasize the diverse functions of LXRs and highlight the potential for small molecules to pharmacologically modulate LXR activity for therapeutic purposes. In the second phase, we conducted an in-silico search for novel LXR modulators, beginning with molecular docking studies of eleven ligands that have been previously tested in preclinical or clinical settings. Based on docking scores and chemico-pharmacokinetic properties, we identified T0901317 and AZ876 as leading candidates, showing the highest binding affinity for LXR-α and LXR-β, respectively. In the final step, we extended our screening to discover new LXR ligands guided by the chemical structures of T0901317 and AZ876. Our docking and molecular dynamics (MD) simulations revealed that ZINC000095464663 and ZINC000021912925 exhibited the strongest binding affinities, alongside favorable pharmacokinetic profiles for both LXR subtypes. In conclusion, our in-silico approach, combining network analysis, virtual screening, molecular docking, MD simulations, and chemico-pharmacokinetic assessments, has uncovered two promising ligands for oral administration, offering potential for future therapeutic interventions targeting LXRs.