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1nlj

From Proteopedia

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{{STRUCTURE_1nlj| PDB=1nlj | SCENE= }}
{{STRUCTURE_1nlj| PDB=1nlj | SCENE= }}
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'''CRYSTAL STRUCTURE OF THE CYSTEINE PROTEASE HUMAN CATHEPSIN K IN COMPLEX WITH A COVALENT AZEPANONE INHIBITOR'''
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===CRYSTAL STRUCTURE OF THE CYSTEINE PROTEASE HUMAN CATHEPSIN K IN COMPLEX WITH A COVALENT AZEPANONE INHIBITOR===
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==Overview==
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The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds show improved configurational stability of the C-4 diastereomeric center relative to the previously published five- and six-membered ring ketone-based inhibitor series. Studies in this series have led to the identification of 20, a potent, selective inhibitor of human cathepsin K (K(i) = 0.16 nM) as well as 24, a potent inhibitor of both human (K(i) = 0.0048 nM) and rat (K(i,app) = 4.8 nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 S stereochemistry as being critical for potent inhibition and that unbound 20 adopted the expected equatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20 to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analogues through CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited by a P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of a conformational constraint has served the dual purpose of increasing inhibitor potency by locking in a bioactive conformation as well as locking out available conformations which may serve as substrates for enzyme systems that limit oral bioavailability.
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{{ABSTRACT_PUBMED_11311061}}
==About this Structure==
==About this Structure==
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[[Category: Hydrolase]]
[[Category: Hydrolase]]
[[Category: Sulfhydryl proteinase]]
[[Category: Sulfhydryl proteinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 03:01:36 2008''

Revision as of 00:01, 28 July 2008

Image:1nlj.png

Template:STRUCTURE 1nlj

CRYSTAL STRUCTURE OF THE CYSTEINE PROTEASE HUMAN CATHEPSIN K IN COMPLEX WITH A COVALENT AZEPANONE INHIBITOR

Template:ABSTRACT PUBMED 11311061

About this Structure

1NLJ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Azepanone-based inhibitors of human and rat cathepsin K., Marquis RW, Ru Y, LoCastro SM, Zeng J, Yamashita DS, Oh HJ, Erhard KF, Davis LD, Tomaszek TA, Tew D, Salyers K, Proksch J, Ward K, Smith B, Levy M, Cummings MD, Haltiwanger RC, Trescher G, Wang B, Hemling ME, Quinn CJ, Cheng HY, Lin F, Smith WW, Janson CA, Zhao B, McQueney MS, D'Alessio K, Lee CP, Marzulli A, Dodds RA, Blake S, Hwang SM, James IE, Gress CJ, Bradley BR, Lark MW, Gowen M, Veber DF, J Med Chem. 2001 Apr 26;44(9):1380-95. PMID:11311061

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