2op3: Difference between revisions
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==Overview== | ==Overview== | ||
The substrate activity screening (SAS) method, a substrate-based fragment | 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. | ||
==About this Structure== | ==About this Structure== | ||
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==Reference== | ==Reference== | ||
Characterization and | Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode., Inagaki H, Tsuruoka H, Hornsby M, Lesley SA, Spraggon G, Ellman JA, J Med Chem. 2007 May 31;50(11):2693-9. Epub 2007 May 1. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17469812 17469812] | ||
[[Category: Cathepsin S]] | [[Category: Cathepsin S]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Ellman, J | [[Category: Ellman, J A.]] | ||
[[Category: Hornsby, M.]] | [[Category: Hornsby, M.]] | ||
[[Category: Inagaki, H.]] | [[Category: Inagaki, H.]] | ||
[[Category: Lesley, S | [[Category: Lesley, S A.]] | ||
[[Category: Spraggon, G.]] | [[Category: Spraggon, G.]] | ||
[[Category: Tsuruoka, H.]] | [[Category: Tsuruoka, H.]] | ||
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[[Category: substrate activity screening]] | [[Category: substrate activity screening]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:21:00 2008'' | ||
Revision as of 16:21, 21 February 2008
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The structure of cathepsin S with a novel 2-arylphenoxyacetaldehyde inhibitor derived by the Substrate Activity Screening (SAS) method
Overview
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.
About this Structure
2OP3 is a Single protein structure of sequence from Homo sapiens with SO4, TF5 and PEU as ligands. Active as Cathepsin S, with EC number 3.4.22.27 Full crystallographic information is available from OCA.
Reference
Characterization and optimization of selective, nonpeptidic inhibitors of cathepsin S with an unprecedented binding mode., Inagaki H, Tsuruoka H, Hornsby M, Lesley SA, Spraggon G, Ellman JA, J Med Chem. 2007 May 31;50(11):2693-9. Epub 2007 May 1. PMID:17469812
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