From Proteopedia
(Difference between revisions)
proteopedia linkproteopedia link
|
|
| Line 1: |
Line 1: |
| - | [[Image:1jh1.jpg|left|200px]] | + | {{Seed}} |
| | + | [[Image:1jh1.png|left|200px]] |
| | | | |
| | <!-- | | <!-- |
| Line 9: |
Line 10: |
| | {{STRUCTURE_1jh1| PDB=1jh1 | SCENE= }} | | {{STRUCTURE_1jh1| PDB=1jh1 | SCENE= }} |
| | | | |
| - | '''Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor'''
| + | ===Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor=== |
| | | | |
| | | | |
| - | ==Overview==
| + | <!-- |
| - | We describe a new generation of heterocyclic nonpeptide matrix metalloproteinase (MMP) inhibitors derived from a 6H-1,3,4-thiadiazine scaffold. A screening effort was utilized to identify some chiral 6-methyl-1,3,4-thiadiazines that are weak inhibitors of the catalytic domain of human neutrophil collagenase (cdMMP-8). Further optimization of the lead compounds revealed general design principles that involve the placement of a phenyl or thienyl group at position 5 of the thiadiazine ring, to improve unprimed side affinity; the incorporation of an amino group at position 2 of the thiadiazine ring as the chelating agent for the catalytic zinc; the placement of a N-sulfonamide-substituted amino acid residue at the amino group, to improve primed side affinity; and the attachment of diverse functional groups at position 4 or 5 of the phenyl or thienyl group at the unprimed side, to improve selectivity. The new compounds were assayed against eight different matrix metalloproteinases, MMP-1, cdMMP-2, cdMMP-8, MMP-9, cdMMP-12, cdMMP-13, cdMMP-14, and the ectodomain of MMP-14, respectively. A unique combination of the above-described modifications produced the selective inhibitor (2R)-N-[5-(4-bromophenyl)-6H-1,3,4-thiadiazin-2-yl]-2-[(phenylsulfonyl)ami no]propanamide with high affinity for MMP-9 (K(i) = 40 nM). X-ray crystallographic data obtained for cdMMP-8 cocrystallized with N-allyl-5-(4-chlorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrobromide gave detailed design information on binding interactions for thiadiazine-based MMP inhibitors.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_11563922}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 11563922 is the PubMed ID number. |
| | + | --> |
| | + | {{ABSTRACT_PUBMED_11563922}} |
| | | | |
| | ==About this Structure== | | ==About this Structure== |
| Line 34: |
Line 38: |
| | [[Category: Inhibitor]] | | [[Category: Inhibitor]] |
| | [[Category: Thiadiazine]] | | [[Category: Thiadiazine]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 21:12:43 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 20:13:52 2008'' |
Revision as of 17:13, 1 July 2008
Template:STRUCTURE 1jh1
Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor
Template:ABSTRACT PUBMED 11563922
About this Structure
1JH1 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold., Schroder J, Henke A, Wenzel H, Brandstetter H, Stammler HG, Stammler A, Pfeiffer WD, Tschesche H, J Med Chem. 2001 Sep 27;44(20):3231-43. PMID:11563922
Page seeded by OCA on Tue Jul 1 20:13:52 2008
