2vin: Difference between revisions

Revision as of 18:52, 4 May 2008

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. 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 Page seeded by OCA on Sun May 4 18:52:47 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
 [[Image:2vin.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2vin |SIZE=350|CAPTION= <scene name='initialview01'>2vin</scene>, resolution 1.9&Aring;
+The line below this paragraph, containing "STRUCTURE_2vin", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=AC1:Act+Binding+Site+For+Chain+A'>AC1</scene>, <scene name='pdbsite=AC2:So4+Binding+Site+For+Chain+A'>AC2</scene> and <scene name='pdbsite=AC3:505+Binding+Site+For+Chain+A'>AC3</scene>
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=505:(2R)-1-(2,6-DIMETHYLPHENOXY)PROPAN-2-AMINE'>505</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[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] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_2vin|  PDB=2vin  |  SCENE=  }}
-|RELATEDENTRY=[[1c5w|1C5W]], [[1c5x|1C5X]], [[1c5y|1C5Y]], [[1c5z|1C5Z]], [[1ejn|1EJN]], [[1fv9|1FV9]], [[1gi7|1GI7]], [[1gi9|1GI9]], [[1gj7|1GJ7]], [[1gj8|1GJ8]], [[1gj9|1GJ9]], [[1gjc|1GJC]], [[1kdu|1KDU]], [[1o5c|1O5C]], [[1owd|1OWD]], [[1owh|1OWH]], [[1owj|1OWJ]], [[1sc8|1SC8]], [[1f5l|1F5L]], [[1f92|1F92]], [[1gi8|1GI8]], [[1gja|1GJA]], [[1gjb|1GJB]], [[1gjd|1GJD]], [[1lmw|1LMW]], [[1o3p|1O3P]], [[1o5a|1O5A]], [[1o5b|1O5B]], [[1owe|1OWE]], [[1owi|1OWI]], [[1owk|1OWK]], [[1sqa|1SQA]], [[1sqo|1SQO]], [[1sqt|1SQT]], [[1u6q|1U6Q]], [[1vj9|1VJ9]], [[1w0z|1W0Z]], [[1w10|1W10]], [[1w12|1W12]], [[1w14|1W14]], [[1vja|1VJA]], [[1w11|1W11]], [[1w13|1W13]], [[2jde|2JDE]], [[2vio|2VIO]], [[2vip|2VIP]], [[2viq|2VIQ]], [[2viv|2VIV]], [[2viw|2VIW]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2vin FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vin OCA], [http://www.ebi.ac.uk/pdbsum/2vin PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2vin RCSB]</span>
-}}
 '''FRAGMENT-BASED DISCOVERY OF MEXILETINE DERIVATIVES AS ORALLY BIOAVAILABLE INHIBITORS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR'''
@@ Line 36: / Line 33: @@
 [[Category: Vinkovic, M.]]
 [[Category: Wallis, N G.]]
-[[Category: blood coagulation]]
+[[Category: Blood coagulation]]
-[[Category: egf-like domain]]
+[[Category: Egf-like domain]]
-[[Category: fibrinolysis]]
+[[Category: Fibrinolysis]]
-[[Category: glycoprotein]]
+[[Category: Glycoprotein]]
-[[Category: hydrolase]]
+[[Category: Hydrolase]]
-[[Category: inhibitor]]
+[[Category: Inhibitor]]
-[[Category: kringle]]
+[[Category: Kringle]]
-[[Category: pharmaceutical]]
+[[Category: Pharmaceutical]]
-[[Category: phosphorylation]]
+[[Category: Phosphorylation]]
-[[Category: plasminogen activation]]
+[[Category: Plasminogen activation]]
-[[Category: polymorphism]]
+[[Category: Polymorphism]]
-[[Category: protease]]
+[[Category: Protease]]
-[[Category: secreted]]
+[[Category: Secreted]]
-[[Category: serine protease]]
+[[Category: Serine protease]]
-[[Category: urokinase-type plasminogen activator]]
+[[Category: Urokinase-type plasminogen activator]]
-[[Category: zymogen]]
+[[Category: Zymogen]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 18:52:47 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:12:47 2008''