Molecular modeling of the interaction of 17(20)Z- and 17(20)E-pregna-5,17(20)-dien-21-oyl amides with the nuclear receptor LXR[beta]

Eight isomeric 17(20)Z- and 17(20)E-pregna-5,17(20)-dien-21-oyl amides, conformationally rigid oxysterol analogues, differing in the structure of the amide moiety have been analyzed. Analysis of low energy conformers revealed that all 17(20)E-isomers had three main energy minima (corresponding to the values of the dihedral angle [theta]^sub 20,21^ (C17=C20-C21=O) about 0°, 120°, and 240°); the most occupied minimum corresponded to [theta]^sub 20,21^ about 0°. 17(20) Z-Isomers had either one or two pools of stable low energy conformations. Molecular docking of these compounds to the ligand-binding site of the nuclear receptor LXR[beta] (a potential target) demonstrated high probability of binding of E-isomers but not Z-isomers with this target. 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)E-3[beta]-hydroxypregna-5,17(20)-dien-21-oyl (hydroxyethyl)amide was demonstrated.[PUBLICATION ABSTRACT]