1jh1

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Revision as of 15:34, 12 November 2007

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spinqualitylabelsall models 1jh1, resolution 2.7Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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.

About this Structure

1JH1 is a Single protein structure of sequence from Homo sapiens with CA, ZN and JST as ligands. Active as Neutrophil collagenase, with EC number 3.4.24.34 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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