Identification of Novel Compounds Targeting the Liver X Receptor (LXR): in-silico studies, screening, molecular docking, and chemico-pharmacokinetic analysis

Abstract

Abstract Background Studies have shown that LXR activity is linked to the development of many diseases, including metabolic diseases. Several LXR agonists have been discovered, but none of the agonists have entered human use due to undesirable side effects. Method In this study, we used multiple biological data repositories (e.g., RNA-seq, human protein atlas, DisGeNET, WebGestalt, and many more) to examine the mRNA and protein expression of LXRs across the tissues and performed network and pathway analysis to redefine their physiological function and disease association. By using in silico research, the current research searches the literature, concentrating on the discovery of new, potentially useful compounds targeting LXRs. We performed molecular docking analysis on LXR agonists that are either approved for preclinical trials or in advanced stages of research. This was carried out using AutoDockTools, ligand-based virtual screening, in-silico studies, screening, molecular docking, and chemico-pharmacokinetic analysis Results Our research implies that the various physiological roles of LXRs and the pharmacological modification of LXRs by small molecules may offer pharmacotherapeutic approaches for disease intervention. After conducting molecular docking analysis and in silico searches, we selected T0901317 and AZ876 for additional screening because they showed the highest affinity for LXR-α and LXR-β. We later conducted a global screening for novel compounds for the LXRs, guided by the previously established chemical structures of T0901317 and AZ876, as well as chemico-pharmacokinetic analysis. Finally, ZINC000095464663 and ZINC000021912925 were found to have the highest binding affinities (− 12.3 and − 11.7 kcal/mol), and potentially useful compounds with favorable chemico-pharmacokinetic features for LXR-α and LXR-β, respectively. Conclusion In summary, the use of SwissSimilarity, molecular docking analysis, and SwissADME for in silico chemico-pharmacokinetic assessment revealed two new and ten previously reported small molecules with potential for oral administration that target LXR-α and LXR-β. This could lead to the development of medium- and long-term pharmacotherapeutic solutions for these molecules.