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: | , , | ||||||
| Activity: | U-plasminogen activator, with EC number 3.4.21.73 | ||||||
| Related: | 1C5W, 1C5X, 1C5Y, 1C5Z, 1EJN, 1FV9, 1GI7, 1GI9, 1GJ7, 1GJ8, 1GJ9, 1GJC, 1KDU, 1O5C, 1OWD, 1OWH, 1OWJ, 1SC8, 1F5L, 1F92, 1GI8, 1GJA, 1GJB, 1GJD, 1LMW, 1O3P, 1O5A, 1O5B, 1OWE, 1OWI, 1OWK, 1SQA, 1SQO, 1SQT, 1U6Q, 1VJ9, 1W0Z, 1W10, 1W12, 1W14, 1VJA, 1W11, 1W13, 2JDE, 2VIO, 2VIP, 2VIQ, 2VIV, 2VIW
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| 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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