Structural basis of prolyl hydroxylase domain inhibition by Molidustat

Journal article

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: Figg, WD; McDonough, MA; Chowdhury, R; Nakashima, Y; Zhang, Z

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: ChemMedChem
• Volume: 16
• Issue: 13
• Pages: 2082-2088
• Place of publication: Germany
• Publication date: 2021-04-09
• Acceptance date: 2021-03-15
• DOI: 10.1002/cmdc.202100133
• EISSN: 1860-7187
• ISSN: 1860-7179
• Pmid: 33792169
• Language: English
• Keywords: hypoxia-inducible factoralpha(HIF); α-ketoglutarate/2-oxoglutarate dependentoxygenase; Roxadustat; Molidustat; anaemia; Vadadustat; prolyl hydroxylase domain / EGLNenzyme inhibition; FFR; Daprodustat