2va5: Difference between revisions

Revision as of 18:28, 4 May 2008

X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 8C

OverviewOverview

Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.

About this StructureAbout this Structure

2VA5 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency., Edwards PD, Albert JS, Sylvester M, Aharony D, Andisik D, Callaghan O, Campbell JB, Carr RA, Chessari G, Congreve M, Frederickson M, Folmer RH, Geschwindner S, Koether G, Kolmodin K, Krumrine J, Mauger RC, Murray CW, Olsson LL, Patel S, Spear N, Tian G, J Med Chem. 2007 Nov 29;50(24):5912-25. Epub 2007 Nov 7. PMID:17985862 Page seeded by OCA on Sun May 4 18:28:18 2008

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

OCA

@@ Line 1: / Line 1: @@
 [[Image:2va5.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2va5 |SIZE=350|CAPTION= <scene name='initialview01'>2va5</scene>, resolution 2.75&Aring;
+The line below this paragraph, containing "STRUCTURE_2va5", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=AC1:Iod+Binding+Site+For+Chain+A'>AC1</scene> and <scene name='pdbsite=AC3:C8c+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=C8C:2-AMINO-6-[2-(1H-INDOL-6-YL)ETHYL]PYRIMIDIN-4(3H)-ONE'>C8C</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_2va5|  PDB=2va5  |  SCENE=  }}
-|RELATEDENTRY=[[1m4h|1M4H]], [[1sgz|1SGZ]], [[1w50|1W50]], [[1w51|1W51]], [[1xs7|1XS7]], [[1ym4|1YM4]], [[1fkn|1FKN]], [[1py1|1PY1]], [[1tqf|1TQF]], [[1ujj|1UJJ]], [[1ujk|1UJK]], [[1xn2|1XN2]], [[1xn3|1XN3]], [[1ym2|1YM2]], [[2b8l|2B8L]], [[2b8v|2B8V]], [[2va6|2VA6]], [[2va7|2VA7]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2va5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2va5 OCA], [http://www.ebi.ac.uk/pdbsum/2va5 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2va5 RCSB]</span>
-}}
 '''X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 8C'''
@@ Line 48: / Line 45: @@
 [[Category: Sylvester, M.]]
 [[Category: Tian, G.]]
-[[Category: alternative splicing]]
+[[Category: Alternative splicing]]
-[[Category: alzheimer's disease]]
+[[Category: Alzheimer's disease]]
-[[Category: aspartic protease]]
+[[Category: Aspartic protease]]
-[[Category: aspartyl protease]]
+[[Category: Aspartyl protease]]
-[[Category: base]]
+[[Category: Base]]
-[[Category: beta-secretase]]
+[[Category: Beta-secretase]]
-[[Category: glycoprotein]]
+[[Category: Glycoprotein]]
-[[Category: hydrolase]]
+[[Category: Hydrolase]]
-[[Category: memapsin 2]]
+[[Category: Memapsin 2]]
-[[Category: membrane]]
+[[Category: Membrane]]
-[[Category: protease]]
+[[Category: Protease]]
-[[Category: transmembrane]]
+[[Category: Transmembrane]]
-[[Category: zymogen]]
+[[Category: Zymogen]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 18:28:18 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:10:19 2008''