2vin
FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR
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| , resolution 1.9Å | |||||||
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| Sites: | , and | ||||||
| Ligands: | , and | ||||||
| Activity: | U-plasminogen activator, with EC number 3.4.21.73 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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. 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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