2vin
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FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR
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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- Homo sapiens
- Single protein
- U-plasminogen activator
- Callaghan, O.
- Chessari, G.
- Congreve, M.
- Cowan, S.R.
- Frederickson, M.
- Matthews, J.E.
- Mcmenamin, R.
- Smith, D.
- Vinkovic, M.
- Wallis, N.G.
- 505
- ACT
- SO4
- Blood coagulation
- Egf-like domain
- Fibrinolysis
- Glycoprotein
- Hydrolase
- Inhibitor
- Kringle
- Pharmaceutical
- Phosphorylation
- Plasminogen activation
- Polymorphism
- Protease
- Secreted
- Serine protease
- Urokinase-type plasminogen activator
- Zymogen