Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat.
Molidustat
anaemia
enzyme inhibition
hypoxia-inducible factor-alpha (HIF)
oxygenases
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
06 07 2021
06 07 2021
Historique:
received:
23
02
2021
pubmed:
2
4
2021
medline:
17
2
2022
entrez:
1
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33792169
doi: 10.1002/cmdc.202100133
pmc: PMC8359944
doi:
Substances chimiques
Prolyl-Hydroxylase Inhibitors
0
Pyrazoles
0
Triazoles
0
molidustat
9JH486CZ13
Prolyl Hydroxylases
EC 1.14.11.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2082-2088Subventions
Organisme : Biotechnology and Biological Research Council
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/L009846/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 106244/Z/14/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Organisme : International Centre
Informations de copyright
© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.
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