1uml

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[[Image:1uml.jpg|left|200px]]<br /><applet load="1uml" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:1uml.jpg|left|200px]]
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caption="1uml, resolution 2.5&Aring;" />
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'''Crystal structure of adenosine deaminase complexed with a potent inhibitor FR233624'''<br />
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{{Structure
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|PDB= 1uml |SIZE=350|CAPTION= <scene name='initialview01'>1uml</scene>, resolution 2.5&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> and <scene name='pdbligand=FR4:1-((1R)-1-(HYDROXYMETHYL)-3-{6-[(3-PHENYLPROPANOYL)AMINO]-1H-INDOL-1-YL}PROPYL)-1H-IMIDAZOLE-4-CARBOXAMIDE'>FR4</scene>
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|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]
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|GENE=
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}}
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'''Crystal structure of adenosine deaminase complexed with a potent inhibitor FR233624'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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1UML is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=FR4:'>FR4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UML OCA].
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1UML is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UML OCA].
==Reference==
==Reference==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15239652 15239652]
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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:[http://www.ncbi.nlm.nih.gov/pubmed/15239652 15239652]
[[Category: Adenosine deaminase]]
[[Category: Adenosine deaminase]]
[[Category: Bos taurus]]
[[Category: Bos taurus]]
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[[Category: zinc]]
[[Category: zinc]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:26:14 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 14:34:00 2008''

Revision as of 12:34, 20 March 2008

Image:1uml.jpg


PDB ID 1uml

Drag the structure with the mouse to rotate
, resolution 2.5Å
Ligands: and
Activity: Adenosine deaminase, with EC number 3.5.4.4
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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