3ZXH

MMP-13 complexed with 2-Napthylsulfonamide hydroxamic acid inhibitor

3ZXH の概要

• エントリーDOI: 10.2210/pdb3zxh/pdb
• 関連するPDBエントリー: 1EUB 1FLS 1FM1 1PEX 1UC1 1XUC 1XUD 1XUR 1YOU 1ZTQ 2D1N 2YIG 456C 830C
• 分子名称: COLLAGENASE 3, ZINC ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: metallo-enzyme, carboxylate inhibitor, collagen degradation, extracellular matrix, hydrolase, metal-binding, metalloprotease
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 40258.44

構造登録者

Clark, K.L.,Kulathila, R. (登録日: 2011-08-10, 公開日: 2011-10-19, 最終更新日: 2024-05-08)

主引用文献

Tommasi, R.A.,Weiler, S.,Mcquire, L.W.,Rogel, O.,Chambers, M.,Clark, K.L.,Doughty, J.,Fang, J.,Ganu, V.,Grob, J.,Goldberg, R.,Goldstein, R.,Lavoie, S.,Kulathila, R.,Macchia, W.,Melton, R.,Springer, C.,Walker, M.,Zhang, J.,Zhu, L.,Shultz, M.
Potent and Selective 2-Naphthylsulfonamide Substituted Hydroxamic Acid Inhibitors of Matrix Metalloproteinase-13.
Bioorg.Med.Chem.Lett., 21:6440-, 2011

PubMed Abstract: The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would provide a disease modifying therapy for the treatment of arthritis, although this goal still continues to elude the pharmaceutical industry due to issues with safety. Our efforts have resulted in the discovery of a series of hydroxamic acid inhibitors of MMP-13 that do not significantly inhibit MMP-2 (gelatinase-1). MMP-2 has been implicated in the musculoskeletal side effects resulting from pan-MMP inhibition due to findings from spontaneously occurring human MMP-2 deletions. Analysis of the SAR of hundreds of previously prepared hydroxamate based MMP inhibitors lead us to 2-naphthylsulfonamide substituted hydroxamates which exhibited modest selectivity for MMP-13 versus MMP-2. This Letter describes the lead optimization of 1 and identification of inhibitors exhibiting >100-fold selectivity for MMP-13 over MMP-2.

PubMed: 21937229
DOI: 10.1016/J.BMCL.2011.08.087

実験手法

X-RAY DIFFRACTION (1.3 Å)