2HXZ

Crystal Structure of Cathepsin S in complex with a Nonpeptidic Inhibitor (Hexagonal spacegroup)

Summary for 2HXZ

• Entry DOI: 10.2210/pdb2hxz/pdb
• Related: 2H7J
• Descriptor: Cathepsin S, SULFATE ION, N-[(1S)-1-{1-[(1R,3E)-1-ACETYLPENT-3-EN-1-YL]-1H-1,2,3-TRIAZOL-4-YL}-1,2-DIMETHYLPROPYL]BENZAMIDE, ... (4 entities in total)
• Functional Keywords: cathepsin s, nonpeptidic, chloromethylketone, substrate activity screening, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P25774
• Total number of polymer chains: 3
• Total formula weight: 74375.66

Authors

Patterson, A.W.,Wood, W.J.,Hornsby, M.,Lesley, S.,Spraggon, G.,Ellman, J.A. (deposition date: 2006-08-04, release date: 2006-10-24, Last modification date: 2023-08-30)

Primary citation

Patterson, A.W.,Wood, W.J.,Hornsby, M.,Lesley, S.,Spraggon, G.,Ellman, J.A.
Identification of selective, nonpeptidic nitrile inhibitors of cathepsin s using the substrate activity screening method.
J.Med.Chem., 49:6298-6307, 2006

PubMed Abstract: The substrate activity screening method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain low nanomolar 1,4-disubstituted-1,2,3-triazole-based aldehyde inhibitors (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). Replacement of the metabolically labile aldehyde pharmacophore with the nitrile pharmacophore provided inhibitors with moderate potency for cathepsin S. The inhibitors showed good selectivity over cathepsins B and L but no selectivity over cathepsin K. X-ray structures of two crystal forms (1.5 and 1.9 A) of a complex between cathepsin S and a triazole inhibitor incorporating a chloromethyl ketone pharmacophore guided the design of triazole substrates with increased cleavage efficiency and selectivity for cathepsin S over cathepsins B, L, and K. Conversion of select substrates to nitrile inhibitors yielded a low molecular weight (414 Da) and potent (15 nM) cathepsin S inhibitor that showed >1000-fold selectivity over cathepsins B, L, and K.

PubMed: 17034136
DOI: 10.1021/jm060701s

Experimental method

X-RAY DIFFRACTION (1.9 Å)