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  • Structural basis of prolyl hydroxylase domain inhibition by molidustat [Elektronski vir]
    Figg, William D. ...
    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 [Pi]-[Pi]-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 [beta2-[beta]3, which are involved in dynamic substrate binding/product release.
    Source: ChemMedChem. - ISSN 1860-7187 (Vol. 16, iss. 13, 2021, str. 2082-2088)
    Type of material - e-article
    Publish date - 2021
    Language - english
    COBISS.SI-ID - 80096771

    Link(s):

    https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202100133

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