Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat.

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.

• Authors: William D Figg Jr, Michael A McDonough, Rasheduzzaman Chowdhury, Yu Nakashima, Zhihong Zhang, James P Holt-Martyn, Alen Krajnc, Christopher J Schofield
• Journal: ChemMedChem (ChemMedChem) Vol. 16 Issue 13 Pg. 2082-2088 (07 06 2021) ISSN: 1860-7187 [Electronic] Germany
• PMID: 33792169 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.

Chemical References

• Prolyl-Hydroxylase Inhibitors
• Pyrazoles
• Triazoles
• molidustat
• Prolyl Hydroxylases

Topics

• Dose-Response Relationship, Drug
• Humans
• Models, Molecular
• Molecular Structure
• Prolyl Hydroxylases (metabolism)
• Prolyl-Hydroxylase Inhibitors (chemistry, pharmacology)
• Pyrazoles (chemistry, pharmacology)
• Structure-Activity Relationship
• Triazoles (chemistry, pharmacology)