2viq: Difference between revisions
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==Overview== | ==Overview== | ||
Fragment-based lead discovery has been applied to urokinase-type | 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 Structure== | ==About this Structure== | ||
2VIQ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ACT:'>ACT</scene> and <scene name='pdbligand=D55:'>D55</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/U-plasminogen_activator U-plasminogen activator], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.73 3.4.21.73] Known structural/functional Sites: <scene name='pdbsite=AC1:Act Binding Site For Chain A'>AC1</scene> and <scene name='pdbsite=AC2:D55 Binding Site For Chain A'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VIQ OCA]. | 2VIQ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ACT:'>ACT</scene> and <scene name='pdbligand=D55:'>D55</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/U-plasminogen_activator U-plasminogen activator], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.73 3.4.21.73] Known structural/functional Sites: <scene name='pdbsite=AC1:Act+Binding+Site+For+Chain+A'>AC1</scene> and <scene name='pdbsite=AC2:D55+Binding+Site+For+Chain+A'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VIQ OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Chessari, G.]] | [[Category: Chessari, G.]] | ||
[[Category: Congreve, M.]] | [[Category: Congreve, M.]] | ||
[[Category: Cowan, S | [[Category: Cowan, S R.]] | ||
[[Category: Frederickson, M.]] | [[Category: Frederickson, M.]] | ||
[[Category: Matthews, J | [[Category: Matthews, J E.]] | ||
[[Category: Mcmenamin, R.]] | [[Category: Mcmenamin, R.]] | ||
[[Category: Smith, D.]] | [[Category: Smith, D.]] | ||
[[Category: Vinkovic, M.]] | [[Category: Vinkovic, M.]] | ||
[[Category: Wallis, N | [[Category: Wallis, N G.]] | ||
[[Category: ACT]] | [[Category: ACT]] | ||
[[Category: D55]] | [[Category: D55]] | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:56:17 2008'' | ||
Revision as of 19:56, 21 February 2008
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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
2VIQ 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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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- 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.
- ACT
- D55
- Blood coagulation
- Egf-like domain
- Fibrinolysis
- Glycoprotein
- Hydrolase
- Inhibitor
- Kringle
- Pharmaceutical
- Phosphorylation
- Plasminogen activation
- Polymorphism
- Protease
- Secreted
- Serine protease
- Urokinase-type plasminogen activator
- Zymogen