6exq

Crystal Structure of Rhodesain in complex with a Macrolactam Inhibitor

spinqualitylabelsall models 6exq, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6exq is a 2 chain structure with sequence from Trypanosoma brucei rhodesiense. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: C2W, EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) -like cysteine protease produced by Trypanosoma brucei (T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors (Ki < 10 nM), preventing the cell-growth of T. b. rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a non-covalent binding mode of this ligand class, due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs. 13.0 for untreated controls) mean days of survival. Repurposing a Library of Human Cathepsin L Ligands: Identification of Macrocyclic Lactams as Potent Rhodesain and Trypanosoma brucei Inhibitors.,Giroud M, Dietzel U, Anselm L, Banner D, Kuglstatter A, Benz J, Blanc JB, Gaufreteau D, Liu H, Lin X, Stich A, Kuhn B, Schuler F, Kaiser M, Brun R, Schirmeister T, Kisker C, Diederich F, Haap W J Med Chem. 2018 Mar 29. doi: 10.1021/acs.jmedchem.7b01869. PMID:29590750 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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