Molecular modeling of interaction of 17(20) and 17(20) E-pregna-5,17(20)-dien-21-oyl amides with the nuclear receptor LXRb

Aiming the search of novel regulators of lipid metabolism and their potential targets, in this study we performed molecular modeling of eight isomeric 17(20) Z - and 17(20) Е -pregna-5,17(20)-dien-21-oyl amides differing in structure of the amide moiety. Analysis of the low energy сonformers revealed that all 17(20) E -isomers had three main energy minima (corresponding to values of the dihedral angle q (С17=C20-C21=O) ~ 0°, ~ 120° and ~ 240°), the most occupied minimum was found to correspond to q ~ 0°; while 17(20) Z -isomers had either one or two pools of low energy conformations. Molecular docking of these compounds to the ligand-binding site of the nuclear receptor LXRb (a potential target) indicates high probability of binding for Е -isomers and the absence of that for Z -isomers. Results of the molecular modeling were confirmed by an experiment in which stimulation of triglyceride biosynthesis in Hep G2 cells in the presence of 17(20) Е -3b-hydroxypregna-5,17(20)-dien-21-оyl (hydroxyethyl)amide was demonstrated.