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1jh1

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{{STRUCTURE_1jh1| PDB=1jh1 | SCENE= }}
{{STRUCTURE_1jh1| PDB=1jh1 | SCENE= }}
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'''Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor'''
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===Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 11563922 is the PubMed ID number.
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{{ABSTRACT_PUBMED_11563922}}
==About this Structure==
==About this Structure==
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[[Category: Inhibitor]]
[[Category: Inhibitor]]
[[Category: Thiadiazine]]
[[Category: Thiadiazine]]
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''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

Image:1jh1.png

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

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