1JH1

Crystal Structure of MMP-8 complexed with a 6H-1,3,4-thiadiazine derived inhibitor

Summary for 1JH1

• Entry DOI: 10.2210/pdb1jh1/pdb
• Descriptor: Matrix Metalloproteinase 8, CALCIUM ION, ZINC ION, ... (5 entities in total)
• Functional Keywords: collagenase, inhibitor, thiadiazine, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasmic granule: P22894
• Total number of polymer chains: 1
• Total formula weight: 18102.88

Authors

Schroder, J.,Henke, A.,Wenzel, H.,Brandstetter, H.,Stammler, H.G.,Stammler, A.,Pfeiffer, W.D.,Tschesche, H. (deposition date: 2001-06-27, release date: 2001-12-27, Last modification date: 2024-04-03)

Primary citation

Schroder, J.,Henke, A.,Wenzel, H.,Brandstetter, H.,Stammler, H.G.,Stammler, A.,Pfeiffer, W.D.,Tschesche, H.
Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold.
J.Med.Chem., 44:3231-3243, 2001

PubMed Abstract: 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)amino]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.

PubMed: 11563922
DOI: 10.1021/jm010887p

Experimental method

X-RAY DIFFRACTION (2.7 Å)