5nrf

Crystal structure of human chitotriosidase-1 (hCHIT) catalytic domain in complex with compound 7i

spinqualitylabelsall models 5nrf, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5nrf is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.447Å Ligands: 95Q, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CHIT1_HUMAN Degrades chitin, chitotriose and chitobiose. May participate in the defense against nematodes and other pathogens. Isoform 3 has no enzymatic activity. Publication Abstract from PubMed This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC50 values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150x against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma. Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma.,Mazur M, Olczak J, Olejniczak S, Koralewski R, Czestkowski W, Jedrzejczak A, Golab J, Dzwonek K, Dymek B, Sklepkiewicz PL, Zagozdzon A, Noonan T, Mahboubi K, Conway B, Sheeler R, Beckett P, Hungerford WM, Podjarny A, Mitschler A, Cousido-Siah A, Fadel F, Golebiowski A J Med Chem. 2018 Feb 8;61(3):695-710. doi: 10.1021/acs.jmedchem.7b01051. Epub, 2018 Jan 11. PMID:29283260 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Chitinase 3D structures

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