2vin

FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR

File:2vin.jpg

spinqualitylabelsall models 2vin, resolution 1.9Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

OverviewOverview

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.

About this StructureAbout this Structure

2VIN is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as U-plasminogen activator, with EC number 3.4.21.73 Known structural/functional Sites: , and . Full crystallographic information is available from OCA.

ReferenceReference

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

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