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2cn0

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{{STRUCTURE_2cn0| PDB=2cn0 | SCENE= }}
{{STRUCTURE_2cn0| PDB=2cn0 | SCENE= }}
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'''COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR'''
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===COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR===
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==Overview==
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In the completion of our fluorine scan of tricyclic inhibitors to map the fluorophilicity/fluorophobicity of the thrombin active site, a series of 11 new ligands featuring alkyl, alkenyl, and fluoroalkyl groups was prepared to explore fluorine effects on binding into the hydrophobic proximal (P) pocket, lined by Tyr 60A and Trp 60D, His 57, and Leu 99. The synthesis of the tricyclic scaffolds was based on the 1,3-dipolar cycloaddition of azomethine ylides, derived from L-proline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide. Introduction of alkyl, alkenyl, and partially fluorinated alkyl residues was achieved upon substitution of a sulfonyl group by mixed Mg/Zn organometallics followed by oxidation/deoxyfluorination, as well as oxidation/reduction/deoxyfluorination sequences. In contrast, the incorporation of perfluoroalkyl groups required a stereoselective nucleophilic addition reaction at the "upper" carbonyl group of the tricycles, thereby yielding scaffolds with an additional OH, F, or OMe group, respectively. All newly prepared inhibitors showed potent biological activity, with inhibitory constants (K(i) values) in the range of 0.008-0.163 microM. The X-ray crystal structure of a protein-ligand complex revealed the exact positioning of a difluoromethyl substituent in the tight P pocket. Fluorophilic characteristics are attributed to this hydrophobic pocket, although the potency of the inhibitors was found to be modulated by steric rather than electronic factors.
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{{ABSTRACT_PUBMED_17001711}}
==About this Structure==
==About this Structure==
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[[Category: Serine protease]]
[[Category: Serine protease]]
[[Category: Serine protease inhibitor complex]]
[[Category: Serine protease inhibitor complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 22:33:06 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 19:56:11 2008''

Revision as of 16:56, 27 July 2008

Image:2cn0.png

Template:STRUCTURE 2cn0

COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR

Template:ABSTRACT PUBMED 17001711

About this Structure

2CN0 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Mapping the fluorophilicity of a hydrophobic pocket: synthesis and biological evaluation of tricyclic thrombin inhibitors directing fluorinated alkyl groups into the p pocket., Hoffmann-Roder A, Schweizer E, Egger J, Seiler P, Obst-Sander U, Wagner B, Kansy M, Banner DW, Diederich F, ChemMedChem. 2006 Nov;1(11):1205-15. PMID:17001711

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