| Author/Editor | Figg, William D.; McDonough, Michael A.; Chowdhury, Rasheduzzaman; Nakashima, Yu; Zhang, Zhihong; Holt-Martyn, James P.; Krajnc, Alen; Schofield, Christopher | |
| Title | Structural basis of prolyl hydroxylase domain inhibition by molidustat | |
| Type | članek | |
| Vol. and No. | Letnik 16, št. 13 | |
| Publication year | 2021 | |
| Volume | str. 2082-2088 | |
| ISSN | 1860-7187 - ChemMedChem | |
| Language | eng | |
| 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 [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. | |
| Descriptors | Ishemija Anemija Hipoksija | |
| Keywords | oksigenaze zaviranje encimov hipoksija faktorja alfa inhibitorji oxygenases anaemia hypoxia-inducible factor-alpha (HIF) Molidustat enzyme inhibition |