2OP3

The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method

Summary for 2OP3

• Entry DOI: 10.2210/pdb2op3/pdb
• Related: 2H7J 2HXZ
• Descriptor: Cathepsin S, SULFATE ION, 2-[(2',3',4'-TRIFLUOROBIPHENYL-2-YL)OXY]ETHANOL, ... (5 entities in total)
• Functional Keywords: cathepsin s, nonpeptidic, substrate activity screening, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P25774
• Total number of polymer chains: 2
• Total formula weight: 50636.77

Authors

Spraggon, G.,Inagaki, H.,Tsuruoka, H.,Hornsby, M.,Lesley, S.A.,Ellman, J.A. (deposition date: 2007-01-26, release date: 2007-05-22, Last modification date: 2024-12-25)

Primary citation

Inagaki, H.,Tsuruoka, H.,Hornsby, M.,Lesley, S.A.,Spraggon, G.,Ellman, J.A.
Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode.
J.Med.Chem., 50:2693-2699, 2007

PubMed Abstract: The substrate activity screening (SAS) method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain a novel (2-arylphenoxy)acetaldehyde inhibitor, 2, with a 0.49 microM Ki value (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). In this paper we disclose the X-ray structure of a complex between cathepsin S and inhibitor 2 which reveals an unprecedented binding mode. On the basis of this structure, additional 2-biaryloxy substrates with greatly increased cleavage efficiency were designed. Conversion of the optimized substrates to the corresponding aldehyde inhibitors yielded a low molecular weight (304 Daltons) and potent (9.6 nM) cathepsin S inhibitor that showed from 100- to >1000-fold selectivity relative to cathepsins B, L, and K.

PubMed: 17469812
DOI: 10.1021/jm070111+

Experimental method

X-RAY DIFFRACTION (1.6 Å)