2hu6: Difference between revisions

Revision as of 06:42, 4 May 2008

Crystal structure of human MMP-12 in complex with acetohydroxamic acid and a bicyclic inhibitor

OverviewOverview

Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12). The molecules obtaining high score were synthesized and the affinity for the catalytic domain of MMP-12 was experimentally proved by NMR experiments. A BTAa scaffold 20 having a N-hydroxyurea group in position 3 and a p-phenylbenzylcarboxy amide in position 7 showed a fair inhibition potency (IC50 = 149 microM) for MMP-12 and some selectivity towards five different MMPs. These results, taken together with the X-ray structure of the adduct between MMP-12, the inhibitor 20 and the acetohydroxamic acid (AHA), suggest that bicyclic scaffold derivatives may be exploited for the design of new selective matrix metalloproteinase inhibitors (MMPIs).

About this StructureAbout this Structure

2HU6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors., Mannino C, Nievo M, Machetti F, Papakyriakou A, Calderone V, Fragai M, Guarna A, Bioorg Med Chem. 2006 Nov 15;14(22):7392-403. Epub 2006 Aug 8. PMID:16899369 Page seeded by OCA on Sun May 4 06:42:55 2008

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

OCA

@@ Line 1: / Line 1: @@
 [[Image:2hu6.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2hu6 |SIZE=350|CAPTION= <scene name='initialview01'>2hu6</scene>, resolution 1.32&Aring;
+The line below this paragraph, containing "STRUCTURE_2hu6", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=37A:(1S,5S,7R)-N~7~-(BIPHENYL-4-YLMETHYL)-N~3~-HYDROXY-6,8-DIOXA-3-AZABICYCLO[3.2.1]OCTANE-3,7-DICARBOXAMIDE'>37A</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=HAE:ACETOHYDROXAMIC+ACID'>HAE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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/Macrophage_elastase Macrophage elastase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.65 3.4.24.65] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= MMP12, HME ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+-->
-|DOMAIN=
+{{STRUCTURE_2hu6|  PDB=2hu6  |  SCENE=  }}
-|RELATEDENTRY=[[1y93|1Y93]], [[1rmz|1RMZ]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2hu6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hu6 OCA], [http://www.ebi.ac.uk/pdbsum/2hu6 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2hu6 RCSB]</span>
-}}
 '''Crystal structure of human MMP-12 in complex with acetohydroxamic acid and a bicyclic inhibitor'''
@@ Line 33: / Line 30: @@
 [[Category: Nievo, M.]]
 [[Category: Papakyriakou, A.]]
-[[Category: drug design]]
+[[Category: Drug design]]
-[[Category: hydroxamic acid]]
+[[Category: Hydroxamic acid]]
-[[Category: inhibitor]]
+[[Category: Inhibitor]]
-[[Category: macrophage metalloelastase]]
+[[Category: Macrophage metalloelastase]]
-[[Category: matrix metalloproteinase]]
+[[Category: Matrix metalloproteinase]]
-[[Category: mmp-12]]
+[[Category: Mmp-12]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 06:42:55 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:35:26 2008''