Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat

William D. Figg, Michael A. McDonough, Rasheduzzaman Chowdhury, Yu Nakashima, Zhihong Zhang, James P. Holt-Martyn, Alen Krajnc, Christopher J. Schofield*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Human prolyl-hydroxylases (PHDs) are hypoxia-sensing 2-oxoglutarate (2OG) oxygenases, catalysis by which suppresses the transcription of hypoxia-inducible factor target genes. PHD inhibition enables the treatment of anaemia/ischaemia-related disease. The PHD inhibitor Molidustat is approved for the treatment of renal anaemia; it differs from other approved/late-stage PHD inhibitors in lacking a glycinamide side chain. The first reported crystal structures of Molidustat and IOX4 (a brain-penetrating derivative) complexed with PHD2 reveal how their contiguous triazole, pyrazolone and pyrimidine/pyridine rings bind at the active site. The inhibitors bind to the active-site metal in a bidentate manner through their pyrazolone and pyrimidine nitrogens, with the triazole π-π-stacking with Tyr303 in the 2OG binding pocket. Comparison of the new structures with other PHD inhibitor complexes reveals differences in the conformations of Tyr303, Tyr310, and a mobile loop linking β2–β3, which are involved in dynamic substrate binding/product release.

Original languageEnglish
Pages (from-to)2082-2088
Number of pages7
JournalChemMedChem
Volume16
Issue number13
DOIs
StatePublished - 2021/07/06

Keywords

  • Molidustat
  • anaemia
  • enzyme inhibition
  • hypoxia-inducible factor-alpha (HIF)
  • oxygenases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • General Pharmacology, Toxicology and Pharmaceutics
  • Organic Chemistry

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