7E0Q
Crystal Structure of Human Indoleamine 2,3-dioxygenagse 1 (hIDO1) Complexed with (1S,2R)-2-(((6-Bromo-1H-indazol-4-yl)amino)methyl)cyclohexan-1-ol (22)
Summary for 7E0Q
| Entry DOI | 10.2210/pdb7e0q/pdb |
| Descriptor | Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, (1~{S},2~{R})-2-[[(6-bromanyl-1~{H}-indazol-4-yl)amino]methyl]cyclohexan-1-ol, ... (4 entities in total) |
| Functional Keywords | indoleamine 2, 3-dioxygenase 1, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 90102.91 |
| Authors | Li, G.-B.,Ning, X.-L. (deposition date: 2021-01-28, release date: 2021-07-21, Last modification date: 2024-10-16) |
| Primary citation | Ning, X.L.,Li, Y.Z.,Huo, C.,Deng, J.,Gao, C.,Zhu, K.R.,Wang, M.,Wu, Y.X.,Yu, J.L.,Ren, Y.L.,Luo, Z.Y.,Li, G.,Chen, Y.,Wang, S.Y.,Peng, C.,Yang, L.L.,Wang, Z.Y.,Wu, Y.,Qian, S.,Li, G.B. X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson's Disease. J.Med.Chem., 64:8303-8332, 2021 Cited by PubMed Abstract: Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to , which manifested IC values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood. PubMed: 34110158DOI: 10.1021/acs.jmedchem.1c00303 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.462 Å) |
Structure validation
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