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

Inaba Y, Yoshimoto N, Sakamaki Y, Nakabayashi M, Ikura T, Tamamura H, Ito N, Shimizu M, Yamamoto K
J Med Chem 52 1438-49 (2009)
Cited: 22 times
EuropePMC logo PMID: 19193059

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.

Articles - 2zxn mentioned but not cited (1)

  1. A multidisciplinary approach disclosing unexplored Aflatoxin B1 roles in severe impairment of vitamin D mechanisms of action. Persico M, Sessa R, Cesaro E, Dini I, Costanzo P, Ritieni A, Fattorusso C, Grosso M. Cell Biol Toxicol 39 1275-1295 (2023)


Reviews citing this publication (8)

  1. Vitamin D and Its Synthetic Analogs. Maestro MA, Molnár F, Carlberg C. J Med Chem 62 6854-6875 (2019)
  2. Vitamin D receptor ligands: the impact of crystal structures. Carlberg C, Molnár F, Mouriño A. Expert Opin Ther Pat 22 417-435 (2012)
  3. Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer. Chai SC, Wright WC, Chen T. Med Res Rev 40 1061-1083 (2020)
  4. Structural considerations of vitamin D signaling. Molnár F. Front Physiol 5 191 (2014)
  5. Multifunctional and potent roles of the 3-hydroxypropoxy group provide eldecalcitol's benefit in osteoporosis treatment. Ono Y. J Steroid Biochem Mol Biol 139 88-97 (2014)
  6. Inhibitors for the Vitamin D Receptor-Coregulator Interaction. Teske KA, Yu O, Arnold LA. Vitam Horm 100 45-82 (2016)
  7. The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands. Maestro MA, Seoane S. Nutrients 14 4927 (2022)
  8. Discovery of Nuclear Receptor Ligands and Elucidation of Their Mechanisms of Action. Yamamoto K. Chem Pharm Bull (Tokyo) 67 609-619 (2019)

Articles citing this publication (13)

  1. Discovery of the first irreversible small molecule inhibitors of the interaction between the vitamin D receptor and coactivators. Nandhikonda P, Lynt WZ, McCallum MM, Ara T, Baranowski AM, Yuan NY, Pearson D, Bikle DD, Guy RK, Arnold LA. J Med Chem 55 4640-4651 (2012)
  2. Peroxisome proliferation-activated receptor δ agonist GW0742 interacts weakly with multiple nuclear receptors, including the vitamin D receptor. Nandhikonda P, Yasgar A, Baranowski AM, Sidhu PS, McCallum MM, Pawlak AJ, Teske K, Feleke B, Yuan NY, Kevin C, Bikle DD, Ayers SD, Webb P, Rai G, Simeonov A, Jadhav A, Maloney D, Arnold LA. Biochemistry 52 4193-4203 (2013)
  3. LXXLL peptide mimetics as inhibitors of the interaction of vitamin D receptor with coactivators. Mita Y, Dodo K, Noguchi-Yachide T, Miyachi H, Makishima M, Hashimoto Y, Ishikawa M. Bioorg Med Chem Lett 20 1712-1717 (2010)
  4. Development of novel Vitamin D Receptor-Coactivator Inhibitors. Sidhu PS, Nassif N, McCallum MM, Teske K, Feleke B, Yuan NY, Nandhikonda P, Cook JM, Singh RK, Bikle DD, Arnold LA. ACS Med Chem Lett 5 199-204 (2014)
  5. Computer-aided de novo ligand design and docking/molecular dynamics study of vitamin D receptor agonists. Shen XL, Takimoto-Kamimura M, Wei J, Gao QZ. J Mol Model 18 203-212 (2012)
  6. Structural development of stapled short helical peptides as vitamin D receptor (VDR)-coactivator interaction inhibitors. Misawa T, Demizu Y, Kawamura M, Yamagata N, Kurihara M. Bioorg Med Chem 23 1055-1061 (2015)
  7. Anticancer activity of VDR-coregulator inhibitor PS121912. Sidhu PS, Teske K, Feleke B, Yuan NY, Guthrie ML, Fernstrum GB, Vyas ND, Han L, Preston J, Bogart JW, Silvaggi NR, Cook JM, Singh RK, Bikle DD, Arnold LA. Cancer Chemother Pharmacol 74 787-798 (2014)
  8. IDENTIFICATION OF VDR ANTAGONISTS AMONG NUCLEAR RECEPTOR LIGANDS USING VIRTUAL SCREENING. Teske K, Nandhikonda P, Bogart JW, Feleke B, Sidhu P, Yuan N, Preston J, Goy R, Han L, Silvaggi NR, Singh RK, Bikle DD, Cook JM, Arnold LA. Nucl Receptor Res 1 101076 (2014)
  9. Novel VDR antagonists based on the GW0742 scaffold. Teske KA, Bogart JW, Arnold LA. Bioorg Med Chem Lett 28 351-354 (2018)
  10. Letter Regulation of the vitamin D receptor by vitamin D lactam derivatives. Asano L, Waku T, Abe R, Kuwabara N, Ito I, Yanagisawa J, Nagasawa K, Shimizu T. FEBS Lett 590 3270-3279 (2016)
  11. SRC2-3 binds to vitamin D receptor with high sensitivity and strong affinity. Egawa D, Itoh T, Kato A, Kataoka S, Anami Y, Yamamoto K. Bioorg Med Chem 25 568-574 (2017)
  12. The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice. Inaba Y, Hashiuchi E, Watanabe H, Kimura K, Oshima Y, Tsuchiya K, Murai S, Takahashi C, Matsumoto M, Kitajima S, Yamamoto Y, Honda M, Asahara SI, Ravnskjaer K, Horike SI, Kaneko S, Kasuga M, Nakano H, Harada K, Inoue H. Nat Commun 14 167 (2023)
  13. Recombinant Expression, Isotope Labeling and Purification of the Vitamin D Receptor Binding Peptide. Chae YK, Singarapu K, Westler WM, Markley JL. Bull Korean Chem Soc 32 4337-4340 (2011)


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