title: Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode.
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.
authors.affiliation: Department of Chemistry, University of California, Berkeley, California 94720, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Inagaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuruoka
authors.forename: Michael
authors.initials: M
authors.lastname: Hornsby
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lesley
authors.forename: Glen
authors.initials: G
authors.lastname: Spraggon
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ellman
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D002403:Cathepsins; C028217:cathepsin S; D000079:Acetaldehyde