Cholestenoic Acid Analogues as Inverse Agonists of the Liver X Receptors

Publication date: Available online 10 January 2020Source: The Journal of Steroid Biochemistry and Molecular BiologyAuthor(s): Lautaro D. Alvarez, María V. Dansey, María F. Ogara, Carina I. Peña, René Houtman, Adriana S. Veleiro, Adali Pecci, Gerardo BurtonAbstractLiver X Receptors (LXRs) are ligand dependent transcription factors activated by oxidized cholesterol metabolites (oxysterols) that play fundamental roles in the transcriptional control of lipid metabolism, cholesterol transport and modulation of inflammatory responses. In the last decade, LXRs have become attractive pharmacological targets for intervention in human metabolic diseases and thus, several efforts have concentrated on the development of synthetic analogues able to modulate LXR transcriptional response. In this sense, we have previously found that cholestenoic acid analogues with a modified side chain behave as LXR inverse agonists. To further investigate the structure-activity relationships and to explore how cholestenoic acid derivatives interact with the LXRs, we evaluated the LXR biological activity of new analogues containing a C24-C25 double bond. Furthermore, a microarray assay was performed to evaluate the recruitment of coregulators to recombinant LXR LBD upon ligand binding. Also, conventional and accelerated molecular dynamics simulations were applied to gain insight on the molecular determinants involved in the inverse agonism. As LXR inverse agonists emerge as very promising candidates to...

Source: The Journal of Steroid Biochemistry and Molecular Biology - January 11, 2020 Category: Biochemistry Source Type: research