1uml
From Proteopedia
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|PDB= 1uml |SIZE=350|CAPTION= <scene name='initialview01'>1uml</scene>, resolution 2.5Å | |PDB= 1uml |SIZE=350|CAPTION= <scene name='initialview01'>1uml</scene>, resolution 2.5Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=FR4:1-((1R)-1-(HYDROXYMETHYL)-3-{6-[(3-PHENYLPROPANOYL)AMINO]-1H-INDOL-1-YL}PROPYL)-1H-IMIDAZOLE-4-CARBOXAMIDE'>FR4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Adenosine_deaminase Adenosine deaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.4.4 3.5.4.4] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Adenosine_deaminase Adenosine deaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.4.4 3.5.4.4] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1o5r|1O5R]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1uml FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1uml OCA], [http://www.ebi.ac.uk/pdbsum/1uml PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1uml RCSB]</span> | ||
}} | }} | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Kinoshita, T.]] | [[Category: Kinoshita, T.]] | ||
| - | [[Category: FR4]] | ||
| - | [[Category: ZN]] | ||
[[Category: beta barrel]] | [[Category: beta barrel]] | ||
[[Category: zinc]] | [[Category: zinc]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:12:22 2008'' |
Revision as of 21:12, 30 March 2008
| |||||||
| , resolution 2.5Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Activity: | Adenosine deaminase, with EC number 3.5.4.4 | ||||||
| Related: | 1O5R
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of adenosine deaminase complexed with a potent inhibitor FR233624
Overview
We disclose herein optimization efforts around the novel, highly potent non-nucleoside adenosine deaminase (ADA) inhibitor, 1-[(R)-1-hydroxy-4-(6-(3-(1-methylbenzimidazol-2-yl)propionylamino)indol-1 -yl)-2-butyl]imidazole-4-carboxamide 1 (K(i)= 7.7 nM), which we recently reported. Structure-based drug design (SBDD) utilizing the crystal structure of the 1/ADA complex was performed in order to obtain structure-activity relationships (SAR) for this type of compound rationally and effectively. To utilize the newly formed hydrophobic space (F2), replacement of the benzimidazole ring of 1 with a n-propyl chain (4b) or a simple phenyl ring (4c) was tolerated in terms of binding activity, and the length of the methylene-spacer was shown to be optimal at two or three. Replacement of an amide with an ether as a linker was also well tolerated in terms of binding activity and moreover improved the oral absorption (6a and 6b). Finally, transformation of indol-1-yl to indol-3-yl resulted in discovery of a novel highly potent and orally bioavailable ADA inhibitor, 1-[(R)-4-(5-(3-(4-chlorophenyl)propoxy)-1-methylindol-3-yl)-1-hydroxy-2-bu tyl]imidazole-4-carboxamide 8c.
About this Structure
1UML is a Single protein structure of sequence from Bos taurus. Full crystallographic information is available from OCA.
Reference
Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors., Terasaka T, Kinoshita T, Kuno M, Seki N, Tanaka K, Nakanishi I, J Med Chem. 2004 Jul 15;47(15):3730-43. PMID:15239652
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