2vio

Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator

spinqualitylabelsall models 2vio, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2vio is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, L1O Related: 1c5x, 1gj9, 1w0z, 1fv9, 1vja, 1gj8, 1w11, 1sqo, 1gjd, 1w10, 1owk, 1w12, 1gi9, 1o5a, 1c5z, 1owj, 1gi7, 1o5b, 1gjc, 1sc8, 1gja, 1o3p, 1owe, 1sqa, 1gjb, 1f92, 1owi, 1kdu, 1sqt, 1f5l, 1owd, 1ejn, 1lmw, 1u6q, 1gi8, 2jde, 1c5y, 1w14, 1vj9, 1w13, 1gj7, 1c5w, 1owh, 1o5c, 2vin, 2vip, 2viq, 2viv, 2viw Activity: U-plasminogen activator, with EC number 3.4.21.73 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [UROK_HUMAN] Defects in PLAU are the cause of Quebec platelet disorder (QPD) [MIM:601709]. QPD is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins. Function [UROK_HUMAN] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Fragment-based lead discovery has been applied to urokinase-type plasminogen activator (uPA). The (R)-enantiomer of the orally active drug mexiletine 5 (a fragment hit from X-ray crystallographic screening) was the chemical starting point. Structure-aided design led to elaborated inhibitors that retained the key interactions of (R)-5 while gaining extra potency by simultaneously occupying neighboring regions of the active site. Subsequent optimization led to 15, a potent, selective, and orally bioavailable inhibitor of uPA. Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.,Frederickson M, Callaghan O, Chessari G, Congreve M, Cowan SR, Matthews JE, McMenamin R, Smith DM, Vinkovic M, Wallis NG J Med Chem. 2008 Jan 24;51(2):183-6. Epub 2007 Dec 29. PMID:18163548 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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