2viw
From Proteopedia
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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== | ||
| - | 2VIW 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=D56:'>D56</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:D56 Binding Site For Chain A'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VIW OCA]. | + | 2VIW 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=D56:'>D56</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:D56+Binding+Site+For+Chain+A'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VIW 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: D56]] | [[Category: D56]] | ||
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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 18:56:19 2008'' |
Revision as of 16:56, 21 February 2008
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FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR
Overview
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
2VIW 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.
Reference
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
Page seeded by OCA on Thu Feb 21 18:56:19 2008
Categories: 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 | D56 | Blood coagulation | Egf-like domain | Fibrinolysis | Glycoprotein | Hydrolase | Inhibitor | Kringle | Pharmaceutical | Phosphorylation | Plasminogen activation | Polymorphism | Protease | Secreted | Serine protease | Urokinase-type plasminogen activator | Zymogen
