7qrc

X-ray structure of Trypanosoma cruzi PEX14 in complex with a PEX5-PEX14 PPI inhibitor

spinqualitylabelsall models 7qrc, resolution 2.18Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7qrc is a 2 chain structure with sequence from Trypanosoma cruzi. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.18Å Ligands: ET7, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A2V2WKZ5_TRYCR Component of the peroxisomal translocation machinery.[RuleBase:RU367032] Publication Abstract from PubMed Trypanosomiases are neglected tropical diseases caused by Trypanosoma (sub)species. Available treatments are limited and have considerable adverse effects and questionable efficacy in the chronic stage of the disease, urgently calling for the identification of new targets and drug candidates. Recently, we have shown that impairment of glycosomal protein import by the inhibition of the PEX5-PEX14 protein-protein interaction (PPI) is lethal to Trypanosoma. Here, we report the development of a novel dibenzo[b,f][1,4]oxazepin-11(10H)-one scaffold for small molecule inhibitors of PEX5-PEX14 PPI. The initial hit was identified by a high throughput screening (HTS) of a library of compounds. A bioisosteric replacement approach allowed to replace the metabolically unstable sulphur atom from the initial dibenzo[b,f][1,4]thiazepin-11(10H)-one HTS hit with oxygen. A crystal structure of the hit compound bound to PEX14 surface facilitated the rational design of the compound series accessible by a straightforward chemistry for the initial structure-activity relationship (SAR) analysis. This guided the design of compounds with trypanocidal activity in cell-based assays providing a promising starting point for the development of new drug candidates to tackle trypanosomiases. Structure-based design, synthesis and evaluation of a novel family of PEX5-PEX14 interaction inhibitors against Trypanosoma.,Napolitano V, Mroz P, Marciniak M, Kalel VC, Softley CA, Janna Olmos JD, Tippler BG, Schorpp K, Rioton S, Frohlich T, Plettenburg O, Hadian K, Erdmann R, Sattler M, Popowicz GM, Dawidowski M, Dubin G Eur J Med Chem. 2022 Dec 5;243:114778. doi: 10.1016/j.ejmech.2022.114778. Epub , 2022 Sep 27. PMID:36194937 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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