1z3n
From Proteopedia
(New page: 200px<br /> <applet load="1z3n" size="450" color="white" frame="true" align="right" spinBox="true" caption="1z3n, resolution 1.04Å" /> '''Human aldose reduct...) |
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| - | [[Image:1z3n.gif|left|200px]]<br /> | + | [[Image:1z3n.gif|left|200px]]<br /><applet load="1z3n" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1z3n" size=" | + | |
caption="1z3n, resolution 1.04Å" /> | caption="1z3n, resolution 1.04Å" /> | ||
'''Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom'''<br /> | '''Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Recent efforts to identify treatments for chronic diabetic complications | + | 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== | ==About this Structure== | ||
| - | 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 NDP and 3NA 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:// | + | 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]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Dicioccio, A | + | [[Category: Dicioccio, A T.]] |
| - | [[Category: Geraci, L | + | [[Category: Geraci, L S.]] |
| - | [[Category: Gunn, D | + | [[Category: Gunn, D E.]] |
| - | [[Category: Jacot, J | + | [[Category: Jacot, J L.]] |
| - | [[Category: Jones, J | + | [[Category: Jones, J H.]] |
| - | [[Category: Jones, M | + | [[Category: Jones, M L.]] |
[[Category: Mitschler, A.]] | [[Category: Mitschler, A.]] | ||
[[Category: Petrova, T.]] | [[Category: Petrova, T.]] | ||
| - | [[Category: Podjarny, A | + | [[Category: Podjarny, A D.]] |
| - | [[Category: Sawicki, D | + | [[Category: Sawicki, D R.]] |
[[Category: Sredy, J.]] | [[Category: Sredy, J.]] | ||
| - | [[Category: Zandt, M | + | [[Category: Zandt, M C.Van.]] |
[[Category: 3NA]] | [[Category: 3NA]] | ||
[[Category: NDP]] | [[Category: NDP]] | ||
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[[Category: oxidoreductase]] | [[Category: oxidoreductase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:11:52 2008'' |
Revision as of 14:11, 21 February 2008
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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 with and as ligands. Active as Aldehyde reductase, with EC number 1.1.1.21 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
Page seeded by OCA on Thu Feb 21 16:11:52 2008
Categories: Aldehyde reductase | Homo sapiens | Single protein | Dicioccio, A T. | Geraci, L S. | Gunn, D E. | Jacot, J L. | Jones, J H. | Jones, M L. | Mitschler, A. | Petrova, T. | Podjarny, A D. | Sawicki, D R. | Sredy, J. | Zandt, M C.Van. | 3NA | NDP | Lidorestat | Nadp+ | Oxidoreductase
