1z3n

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[[Image:1z3n.gif|left|200px]]<br /><applet load="1z3n" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:1z3n.gif|left|200px]]
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caption="1z3n, resolution 1.04&Aring;" />
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'''Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom'''<br />
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{{Structure
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|PDB= 1z3n |SIZE=350|CAPTION= <scene name='initialview01'>1z3n</scene>, resolution 1.04&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene> and <scene name='pdbligand=3NA:{3-[(4,5,7-TRIFLUORO-1,3-BENZOTHIAZOL-2-YL)METHYL]-1H-INDOL-1-YL}ACETIC ACID'>3NA</scene>
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|ACTIVITY= [http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21]
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|GENE=
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}}
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'''Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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1Z3N is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NDP:'>NDP</scene> and <scene name='pdbligand=3NA:'>3NA</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Aldehyde_reductase Aldehyde reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.21 1.1.1.21] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Z3N OCA].
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1Z3N is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Z3N OCA].
==Reference==
==Reference==
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Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications., Van Zandt MC, Jones ML, Gunn DE, Geraci LS, Jones JH, Sawicki DR, Sredy J, Jacot JL, Dicioccio AT, Petrova T, Mitschler A, Podjarny AD, J Med Chem. 2005 May 5;48(9):3141-52. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15857120 15857120]
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Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications., Van Zandt MC, Jones ML, Gunn DE, Geraci LS, Jones JH, Sawicki DR, Sredy J, Jacot JL, Dicioccio AT, Petrova T, Mitschler A, Podjarny AD, J Med Chem. 2005 May 5;48(9):3141-52. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15857120 15857120]
[[Category: Aldehyde reductase]]
[[Category: Aldehyde reductase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: oxidoreductase]]
[[Category: oxidoreductase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:11:52 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 15:30:51 2008''

Revision as of 13:30, 20 March 2008

Image:1z3n.gif


PDB ID 1z3n

Drag the structure with the mouse to rotate
, resolution 1.04Å
Ligands: and
Activity: Aldehyde reductase, with EC number 1.1.1.21
Coordinates: save as pdb, mmCIF, xml



Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom


Overview

Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC(50) of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED(50)'s of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t(1/2), 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (C(max) in sciatic nerve and eye are 2.36 and 1.45 mug equiv/g, respectively, when dosed with [(14)C]lidorestat at 10 mg/kg po).

About this Structure

1Z3N is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications., Van Zandt MC, Jones ML, Gunn DE, Geraci LS, Jones JH, Sawicki DR, Sredy J, Jacot JL, Dicioccio AT, Petrova T, Mitschler A, Podjarny AD, J Med Chem. 2005 May 5;48(9):3141-52. PMID:15857120

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