A new class of vitamin D analogues that induce structural rearrangement of the ligand-binding pocket of the receptor

Yuka Inaba; Nobuko Yoshimoto; Yuta Sakamaki; Makoto Nakabayashi; Teikichi Ikura; Hirokazu Tamamura; Nobutoshi Ito; Masato Shimizu; Keiko Yamamoto

doi:10.1021/jm8014348

A new class of vitamin D analogues that induce structural rearrangement of the ligand-binding pocket of the receptor

J Med Chem. 2009 Mar 12;52(5):1438-49. doi: 10.1021/jm8014348.

Authors

Yuka Inaba¹, Nobuko Yoshimoto, Yuta Sakamaki, Makoto Nakabayashi, Teikichi Ikura, Hirokazu Tamamura, Nobutoshi Ito, Masato Shimizu, Keiko Yamamoto

Affiliation

¹ Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Tokyo, Japan.

PMID: 19193059
DOI: 10.1021/jm8014348

Abstract

To identify novel vitamin D receptor (VDR) ligands that induce a novel architecture within the ligand-binding pocket (LBP), we have investigated eight 22-butyl-1alpha,24-dihydroxyvitamin D(3) derivatives (3-10), all having a butyl group as the branched alkyl side chain. We found that the 22S-butyl-20-epi-25,26,27-trinorvitamin D derivative 5 was a potent VDR agonist, whereas the corresponding compound 4 with the natural configuration at C(20) was a potent VDR antagonist. Analogues with the full vitamin D(3) side chain were less potent agonist, and whether they were agonists or antagonists depended on the 24-configuration. X-ray crystal structures demonstrated that the VDR-LBD accommodating the potent agonist 5 has an architecture wherein the lower side and the helix 11 side of the LBP is simply expanded relative to the canonical active-VDR situation; in contrast, the potent antagonist 4 induces an extra cavity to accommodate the branched moiety. This is the first report of a VDR antagonist that generates a new cavity to alter the canonical pocket structure of the ligand occupied VDR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Binding Sites
Binding, Competitive
Calcitriol / analogs & derivatives*
Calcitriol / chemical synthesis*
Calcitriol / pharmacology
Cattle
Cell Differentiation / drug effects
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Chlorocebus aethiops
Cholecalciferol / analogs & derivatives*
Cholecalciferol / chemical synthesis
Cholecalciferol / pharmacology
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Genes, Reporter
Humans
Ligands
Models, Molecular
Nuclear Receptor Coactivator 1 / metabolism
Receptors, Calcitriol / agonists*
Receptors, Calcitriol / antagonists & inhibitors*
Receptors, Calcitriol / genetics
Retinoid X Receptors / metabolism
Stereoisomerism
Steroid Hydroxylases / biosynthesis
Structure-Activity Relationship
Transcription, Genetic / drug effects
Vitamin D3 24-Hydroxylase

Substances

22-butyl-1,24-dihydroxy-24,25,26-trinorvitamin D3
Antineoplastic Agents
Ligands
Receptors, Calcitriol
Retinoid X Receptors
Cholecalciferol
Steroid Hydroxylases
Vitamin D3 24-Hydroxylase
Nuclear Receptor Coactivator 1
Calcitriol