1KYN

Cathepsin-G

Summary for 1KYN

• Entry DOI: 10.2210/pdb1kyn/pdb
• Descriptor: cathepsin G, (2-NAPHTHALEN-2-YL-1-NAPHTHALEN-1-YL-2-OXO-ETHYL)-PHOSPHONIC ACID (2 entities in total)
• Functional Keywords: serine protease, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cell surface: P08311
• Total number of polymer chains: 2
• Total formula weight: 54356.26

Authors

Greco, M.N.,Hawkins, M.J.,Powell, E.T.,Almond Jr., H.R.,Corcoran, T.W.,De Garavilla, L.,Kauffman, J.A.,Recacha, R.,Chattopadhyay, D.,Andrade-Gordon, P.,Maryanoff, B.E. (deposition date: 2002-02-05, release date: 2002-05-01, Last modification date: 2024-10-30)

Primary citation

Greco, M.N.,Hawkins, M.J.,Powell, E.T.,Almond Jr., H.R.,Corcoran, T.W.,de Garavilla, L.,Kauffman, J.A.,Recacha, R.,Chattopadhyay, D.,Andrade-Gordon, P.,Maryanoff, B.E.
Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design.
J.Am.Chem.Soc., 124:3810-3811, 2002

PubMed Abstract: 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.

PubMed: 11942800
DOI: 10.1021/ja017506h

Experimental method

X-RAY DIFFRACTION (3.5 Å)