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Structure-based design of a superagonist ligand for the vitamin D nuclear receptor.

Hourai S, Rodrigues LC, Antony P, Reina-San-Martin B, Ciesielski F, Magnier BC, Schoonjans K, Mouriño A, Rochel N, Moras D
Chem Biol 15 383-92 (2008)
Cited: 20 times
EuropePMC logo PMID: 18420145

Abstract

Vitamin D nuclear receptor (VDR), a ligand-dependent transcriptional regulator, is an important target for multiple clinical applications, such as osteoporosis and cancer. Since exacerbated increase of calcium serum level is currently associated with VDR ligands action, superagonists with low calcium serum levels have been developed. Based on the crystal structures of human VDR (hVDR) bound to 1alpha,25-dihydroxyvitamin D(3) and superagonists-notably, KH1060-we designed a superagonist ligand. In order to optimize the aliphatic side chain conformation with a subsequent entropy benefit, we incorporated an oxolane ring and generated two stereo diasteromers, AMCR277A and AMCR277B. Only AMCR277A exhibits superagonist activity in vitro, but is as calcemic in vivo as the natural ligand. The crystal structures of the complexes between the ligand binding domain of hVDR and these ligands provide a rational approach to the design of more potent superagonist ligands for potential clinical application.

Articles - 3cs6 mentioned but not cited (2)

  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)
  2. Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia. Khedkar SA, Samad MA, Choudhury S, Lee JY, Zhang D, Thadhani RI, Karumanchi SA, Rigby AC, Kang PM. Sci Rep 7 8427 (2017)


Reviews citing this publication (9)

  1. Anticancer steroids: linking natural and semi-synthetic compounds. Salvador JA, Carvalho JF, Neves MA, Silvestre SM, Leitão AJ, Silva MM, Sá e Melo ML. Nat Prod Rep 30 324-374 (2013)
  2. Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment. Tebben PJ, Singh RJ, Kumar R. Endocr. Rev. 37 521-547 (2016)
  3. Vitamin D receptor ligands: the impact of crystal structures. Carlberg C, Molnár F, Mouriño A. Expert Opin Ther Pat 22 417-435 (2012)
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  5. 3D structures and ligand specificities of nuclear xenobiotic receptors CAR, PXR and VDR. Wu B, Li S, Dong D. Drug Discov. Today 18 574-581 (2013)
  6. Superagonism at G protein-coupled receptors and beyond. Schrage R, De Min A, Hochheiser K, Kostenis E, Mohr K. Br. J. Pharmacol. 173 3018-3027 (2016)
  7. New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues. Pike JW, Meyer MB. Int J Mol Sci 22 12352 (2021)
  8. The Use of Vitamin D Metabolites and Analogues in the Treatment of Chronic Kidney Disease. Zand L, Kumar R. Endocrinol. Metab. Clin. North Am. 46 983-1007 (2017)
  9. The Centennial Collection of VDR Ligands: Metabolites, Analogs, Hybrids and Non-Secosteroidal Ligands. Maestro MA, Seoane S. Nutrients 14 4927 (2022)

Articles citing this publication (9)

  1. Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA. Orlov I, Rochel N, Moras D, Klaholz BP. EMBO J. 31 291-300 (2012)
  2. Crystal structure of CYP24A1, a mitochondrial cytochrome P450 involved in vitamin D metabolism. Annalora AJ, Goodin DB, Hong WX, Zhang Q, Johnson EF, Stout CD. J. Mol. Biol. 396 441-451 (2010)
  3. 1α,25(OH)2-3-epi-vitamin D3, a natural physiological metabolite of vitamin D3: its synthesis, biological activity and crystal structure with its receptor. Molnár F, Sigüeiro R, Sato Y, Araujo C, Schuster I, Antony P, Peluso J, Muller C, Mouriño A, Moras D, Rochel N. PLoS ONE 6 e18124 (2011)
  4. A human vitamin D receptor mutant activated by cholecalciferol. Ousley AM, Castillo HS, Duraj-Thatte A, Doyle DF, Azizi B. J. Steroid Biochem. Mol. Biol. 125 202-210 (2011)
  5. Design, synthesis, evaluation, and structure of vitamin D analogues with furan side chains. Fraga R, Zacconi F, Sussman F, Ordóñez-Morán P, Muñoz A, Huet T, Molnár F, Moras D, Rochel N, Maestro M, Mouriño A. Chemistry 18 603-612 (2012)
  6. Efficient stable isotope labeling and purification of vitamin D receptor from inclusion bodies. Zhu J, Rao H, Tonelli M, Westler WM, Singarapu KK, Markley JL, DeLuca HF, Assadi-Porter FM. Protein Expr. Purif. 85 25-31 (2012)
  7. Structure-activity relationship study of vitamin D analogs with oxolane group in their side chain. Belorusova AY, Martínez A, Gándara Z, Gómez G, Fall Y, Rochel N. Eur J Med Chem 134 86-96 (2017)
  8. Novel calcitriol analogue with an oxolane group: In vitro, in vivo, and in silico studies. Obiol DJ, Martínez A, Ferronato MJ, Quevedo MA, Grioli SM, Alonso EN, Gómez G, Fall Y, Facchinetti MM, Curino AC. Arch Pharm (Weinheim) 352 e1800315 (2019)
  9. Vitamin D and Its Synthetic Analogs. Maestro MA, Molnár F, Carlberg C. J. Med. Chem. 62 6854-6875 (2019)


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