1jh1

From Proteopedia

Revision as of 14:07, 15 February 2008

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 , and 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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