2cn0: Difference between revisions
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==Overview== | ==Overview== | ||
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. | 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. | ||
==Disease== | |||
Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: serine protease inhibitor complex]] | [[Category: serine protease inhibitor complex]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:17:24 2007'' | ||
Revision as of 22:10, 12 November 2007
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COMPLEX OF RECOMBINANT HUMAN THROMBIN WITH A DESIGNED INHIBITOR
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
2CN0 is a Protein complex structure of sequences from Homo sapiens with NA, CA, F25 and SIN as ligands. Active as Thrombin, with EC number 3.4.21.5 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
ReferenceReference
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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