5ZFI

Mouse kallikrein 7 in complex with 6-benzyl-1,4-diazepan-7-one derivative

Summary for 5ZFI

• Entry DOI: 10.2210/pdb5zfi/pdb
• Related: 5zfh
• Descriptor: Kallikrein-7, 2-[(3Z,6R)-6-[(2,6-dichlorophenyl)methyl]-3-(dimethylhydrazinylidene)-7-oxo-1,4-diazepan-1-yl]-N-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]acetamide, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (4 entities in total)
• Functional Keywords: protease, inhibitor complex, hydrolase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 25301.94

Authors

Sugawara, H. (deposition date: 2018-03-06, release date: 2018-06-27, Last modification date: 2024-11-13)

Primary citation

Murafuji, H.,Sugawara, H.,Goto, M.,Oyama, Y.,Sakai, H.,Imajo, S.,Tomoo, T.,Muto, T.
Structure-based drug design to overcome species differences in kallikrein 7 inhibition of 1,3,6-trisubstituted 1,4-diazepan-7-ones.
Bioorg. Med. Chem., 26:3639-3653, 2018

PubMed Abstract: A series of 1,3,6-trisubstituted 1,4-diazepan-7-ones were prepared as kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Previously reported compounds 1-3 were potent human KLK7 inhibitors; however, they did not exhibit inhibitory activity against mouse KLK7. Comparison of the human and mouse KLK7 structures reveals the cause of this species differences; therefore, compounds that could inhibit both KLK7s were designed, synthesized, and evaluated. Through this structure-based drug design, compound 22g was identified as an inhibitor against human and mouse KLK7, and only one of the enantiomers, (-)-22g, exhibited potent inhibitory activity. Furthermore, the crystal structure of mouse KLK7 complexed with 22g enabled the elucidation of structure-activity relationships and justified 22g as a valuable compound to overcome the species differences.

PubMed: 29884582
DOI: 10.1016/j.bmc.2018.05.044

Experimental method

X-RAY DIFFRACTION (1.8 Å)