1JH1

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

1JH1 の概要

• エントリーDOI: 10.2210/pdb1jh1/pdb
• 分子名称: Matrix Metalloproteinase 8, CALCIUM ION, ZINC ION, ... (5 entities in total)
• 機能のキーワード: collagenase, inhibitor, thiadiazine, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasmic granule: P22894
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18102.88

構造登録者

Schroder, J.,Henke, A.,Wenzel, H.,Brandstetter, H.,Stammler, H.G.,Stammler, A.,Pfeiffer, W.D.,Tschesche, H. (登録日: 2001-06-27, 公開日: 2001-12-27, 最終更新日: 2024-04-03)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.7 Å)