1kyn
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in | + | The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified beta-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC(50) = 4.1 microM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 A). Structural details from the X-ray analysis of 1.Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC(50) = 53 nM). From these results, it is evident that the beta-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors. |
==About this Structure== | ==About this Structure== | ||
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[[Category: Andrade-Gordon, P.]] | [[Category: Andrade-Gordon, P.]] | ||
[[Category: Chattopadhyay, D.]] | [[Category: Chattopadhyay, D.]] | ||
| - | [[Category: Corcoran, T | + | [[Category: Corcoran, T W.]] |
| - | [[Category: Garavilla, L | + | [[Category: Garavilla, L De.]] |
| - | [[Category: Greco, M | + | [[Category: Greco, M N.]] |
| - | [[Category: Hawkins, M | + | [[Category: Hawkins, M J.]] |
| - | [[Category: Jr., H | + | [[Category: Jr., H R.Almond.]] |
| - | [[Category: Kauffman, J | + | [[Category: Kauffman, J A.]] |
| - | [[Category: Maryanoff, B | + | [[Category: Maryanoff, B E.]] |
| - | [[Category: Powell, E | + | [[Category: Powell, E T.]] |
[[Category: Recacha, R.]] | [[Category: Recacha, R.]] | ||
[[Category: KTP]] | [[Category: KTP]] | ||
[[Category: serine protease]] | [[Category: serine protease]] | ||
| - | ''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 13:39:20 2008'' |
Revision as of 11:39, 21 February 2008
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Cathepsin-G
Overview
The serine protease cathepsin G (EC 3.4.21.20; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified beta-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC(50) = 4.1 microM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 A). Structural details from the X-ray analysis of 1.Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC(50) = 53 nM). From these results, it is evident that the beta-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors.
About this Structure
1KYN is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Cathepsin G, with EC number 3.4.21.20 Full crystallographic information is available from OCA.
Reference
Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design., Greco MN, Hawkins MJ, Powell ET, Almond HR Jr, Corcoran TW, de Garavilla L, Kauffman JA, Recacha R, Chattopadhyay D, Andrade-Gordon P, Maryanoff BE, J Am Chem Soc. 2002 Apr 17;124(15):3810-1. PMID:11942800
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