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| {{STRUCTURE_1veb| PDB=1veb | SCENE= }} | | {{STRUCTURE_1veb| PDB=1veb | SCENE= }} |
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| '''Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 5'''
| | ===Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 5=== |
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| ==Overview==
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| Novel azepane derivatives were prepared and evaluated for protein kinase B (PKB-alpha) and protein kinase A (PKA) inhibition. The original (-)-balanol-derived lead structure (4R)-4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R)-3-[(pyridine-4-carbonyl)amino]-azepan-4-yl ester (1) (IC(50) (PKB-alpha) = 5 nM) which contains an ester moiety was found to be plasma unstable and therefore unsuitable as a drug. Based upon molecular modeling studies using the crystal structure of the complex between PKA and 1, the five compounds N-[(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]-azepa n-3-yl]-isonicotinamide (4), (3R,4R)-N-[4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzyloxy]-azepan-3 -yl]-isonicotinamide (5), N-[(3R,4S)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenylamino]-methyl ]-azepan-3-yl)-isonicotinamide (6), N-[(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzylamino]-azepan -3-yl]-isonicotinamide (7), and N-[(3R,4S)-4-(4-[trans-2-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenyl] -vinyl]-azepan-3-yl)-isonicotinamide (8) with linkers isosteric to the ester were designed, synthesized, and tested for in vitro inhibitory activity against PKA and PKB-alpha and for plasma stability in mouse plasma.(1) Compound 4 was found to be plasma stable and highly active (IC(50) (PKB-alpha) = 4 nM). Cocrystals with PKA were obtained for 4, 5, and 8 and analyzed for binding interactions and conformational changes in the ligands and protein in order to rationalize the different activities of the molecules.
| | The line below this paragraph, {{ABSTRACT_PUBMED_14998327}}, adds the Publication Abstract to the page |
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| | {{ABSTRACT_PUBMED_14998327}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Kinase-inhibitor-complex]] | | [[Category: Kinase-inhibitor-complex]] |
| [[Category: Serine/threonine-protein kinase]] | | [[Category: Serine/threonine-protein kinase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 12:26:25 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 17:07:09 2008'' |
