1svh
From Proteopedia
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'''Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 8''' | '''Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 8''' | ||
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[[Category: Thomas, U.]] | [[Category: Thomas, U.]] | ||
[[Category: Wegge, T.]] | [[Category: Wegge, T.]] | ||
| - | [[Category: | + | [[Category: Balanol derivative]] |
| - | [[Category: | + | [[Category: Kinase-inhibitor-complex]] |
| - | [[Category: | + | [[Category: Serine/threonine-protein kinase]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 09:10:51 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 06:10, 3 May 2008
Crystal Structure of Protein Kinase A in Complex with Azepane Derivative 8
Overview
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.
About this Structure
1SVH is a Protein complex structure of sequences from Bos taurus. Full crystallographic information is available from OCA.
Reference
Structure-based optimization of novel azepane derivatives as PKB inhibitors., Breitenlechner CB, Wegge T, Berillon L, Graul K, Marzenell K, Friebe WG, Thomas U, Schumacher R, Huber R, Engh RA, Masjost B, J Med Chem. 2004 Mar 11;47(6):1375-90. PMID:14998327 Page seeded by OCA on Sat May 3 09:10:51 2008
Categories: Bos taurus | Non-specific serine/threonine protein kinase | Protein complex | Berillon, L. | Breitenlechner, C B. | Engh, R A. | Friebe, W G. | Graul, K. | Huber, R. | Marzenell, K. | Masjost, B. | Schumacher, R. | Thomas, U. | Wegge, T. | Balanol derivative | Kinase-inhibitor-complex | Serine/threonine-protein kinase
