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 LXRβ

• Published in: Biochemistry (Moscow). Supplement. Series B, Biomedical chemistry Biomedical chemistry, 2013-07, Vol.7 (3), p.196-201
• Main Authors: Fedyushkina, I. V., Stulov, S. V., Dugin, N. O., Misharin, A. Yu, Mehtiev, A. R., Morozevich, G. E., Veselovsky, A. V.
• Format: Article
• Language: English
• Subjects: Bioorganic Chemistry; Chemistry; Chemistry and Materials Science; Medicinal Chemistry
• ISSN: 1990-7508; 1990-7516
• DOI: 10.1134/S1990750813030037

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 θ 20,21 (C17=C20-C21=O) about ∼0°, ∼120°, and ∼240°); the most occupied minimum corresponded to θ 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 LXRβ (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 -3β-hydroxypregna-5,17(20)-dien-21-oyl (hydroxyethyl)amide was demonstrated.