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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-articlePublish date - 2021Language - englishCOBISS.SI-ID - 80096771
Author
Figg, William D. |
McDonough, Michael A. |
Chowdhury, Rasheduzzaman |
Nakashima, Yu |
Zhang, Zhihong |
Holt-Martyn, James P. |
Krajnc, Alen, Farmacija, 1994 |
Schofield, Christopher
Topics
Ishemija |
Anemija |
Hipoksija |
oksigenaze |
zaviranje encimov |
hipoksija faktorja alfa |
inhibitorji |
oxygenases |
anaemia |
hypoxia-inducible factor-alpha (HIF) |
Molidustat |
enzyme inhibition
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Figg, William D. | |
McDonough, Michael A. | |
Chowdhury, Rasheduzzaman | |
Nakashima, Yu | |
Zhang, Zhihong | |
Holt-Martyn, James P. | |
Krajnc, Alen, Farmacija, 1994 | 55572 |
Schofield, Christopher |
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