Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T26623 | Target Info | |||
| Target Name | Aldose reductase (AKR1B1) | ||||
| Synonyms | Aldehyde reductase; AKR1B1 | ||||
| Target Type | Successful Target | ||||
| Gene Name | AKR1B1 | ||||
| Biochemical Class | Short-chain dehydrogenases reductase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Fidarestat | Ligand Info | |||
| Canonical SMILES | C1C(OC2=C(C13C(=O)NC(=O)N3)C=C(C=C2)F)C(=O)N | ||||
| InChI | 1S/C12H10FN3O4/c13-5-1-2-7-6(3-5)12(4-8(20-7)9(14)17)10(18)15-11(19)16-12/h1-3,8H,4H2,(H2,14,17)(H2,15,16,18,19)/t8-,12-/m0/s1 | ||||
| InChIKey | WAAPEIZFCHNLKK-UFBFGSQYSA-N | ||||
| PubChem Compound ID | 160024 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 2PF8 Complex of Aldose Reductase with NADP+ and simaltaneously bound competetive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution is equal to concentration of IDD594. | ||||||
| Method | X-ray diffraction | Resolution | 0.85 Å | Mutation | No | [1] |
| PDB Sequence |
MASRILLNNG
9 AKMPILGLGT19 WKSPPGQVTE29 AVKVAIDVGY39 RHIDCAHVYQ49 NENEVGVAIQ 59 EKLREQVVKR69 EELFIVSKLW79 CTYHEKGLVK89 GACQKTLSDL99 KLDYLDLYLI 109 HWPTGFKPGK119 EFFPLDESGN129 VVPSDTNILD139 TWAAMEELVD149 EGLVKAIGIS 159 NFNHLQVEMI169 LNKPGLKYKP179 AVNQIECHPY189 LTQEKLIQYC199 QSKGIVVTAY 209 SPLGSPDRPW219 AKPEDPSLLE229 DPRIKAIAAK239 HNKTTAQVLI249 RFPMQRNLVV 259 IPKSVTPERI269 AENFKVFDFE279 LSSQDMTTLL289 SYNRNWRVCA299 LLSCTSHKDY 309 PFHEEF
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| PDB ID: 2PFH Complex of Aldose Reductase with NADP+ and simaltaneously bound competetive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution is less than concentration of IDD594. | ||||||
| Method | X-ray diffraction | Resolution | 0.85 Å | Mutation | No | [1] |
| PDB Sequence |
MASRILLNNG
9 AKMPILGLGT19 WKSPPGQVTE29 AVKVAIDVGY39 RHIDCAHVYQ49 NENEVGVAIQ 59 EKLREQVVKR69 EELFIVSKLW79 CTYHEKGLVK89 GACQKTLSDL99 KLDYLDLYLI 109 HWPTGFKPGK119 EFFPLDESGN129 VVPSDTNILD139 TWAAMEELVD149 EGLVKAIGIS 159 NFNHLQVEMI169 LNKPGLKYKP179 AVNQIECHPY189 LTQEKLIQYC199 QSKGIVVTAY 209 SPLGSPDRPW219 AKPEDPSLLE229 DPRIKAIAAK239 HNKTTAQVLI249 RFPMQRNLVV 259 IPKSVTPERI269 AENFKVFDFE279 LSSQDMTTLL289 SYNRNWRVCA299 LLSCTSHKDY 309 PFHE
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| PDB ID: 2PEV Complex of Aldose Reductase with NADP+ and simaltaneously bound competetive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution exceeds concentration of IDD594. | ||||||
| Method | X-ray diffraction | Resolution | 0.90 Å | Mutation | No | [1] |
| PDB Sequence |
MASRILLNNG
9 AKMPILGLGT19 WKSPPGQVTE29 AVKVAIDVGY39 RHIDCAHVYQ49 NENEVGVAIQ 59 EKLREQVVKR69 EELFIVSKLW79 CTYHEKGLVK89 GACQKTLSDL99 KLDYLDLYLI 109 HWPTGFKPGK119 EFFPLDESGN129 VVPSDTNILD139 TWAAMEELVD149 EGLVKAIGIS 159 NFNHLQVEMI169 LNKPGLKYKP179 AVNQIECHPY189 LTQEKLIQYC199 QSKGIVVTAY 209 SPLGSPDRPW219 AKPEDPSLLE229 DPRIKAIAAK239 HNKTTAQVLI249 RFPMQRNLVV 259 IPKSVTPERI269 AENFKVFDFE279 LSSQDMTTLL289 SYNRNWRVCA299 LLSCTSHKDY 309 PFHEEF
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| PDB ID: 1PWM Crystal structure of human Aldose Reductase complexed with NADP and Fidarestat | ||||||
| Method | X-ray diffraction | Resolution | 0.92 Å | Mutation | No | [2] |
| PDB Sequence |
MASRILLNNG
9 AKMPILGLGT19 WKSPPGQVTE29 AVKVAIDVGY39 RHIDCAHVYQ49 NENEVGVAIQ 59 EKLREQVVKR69 EELFIVSKLW79 CTYHEKGLVK89 GACQKTLSDL99 KLDYLDLYLI 109 HWPTGFKPGK119 EFFPLDESGN129 VVPSDTNILD139 TWAAMEELVD149 EGLVKAIGIS 159 NFNHLQVEMI169 LNKPGLKYKP179 AVNQIECHPY189 LTQEKLIQYC199 QSKGIVVTAY 209 SPLGSPDRPW219 AKPEDPSLLE229 DPRIKAIAAK239 HNKTTAQVLI249 RFPMQRNLVV 259 IPKSVTPERI269 AENFKVFDFE279 LSSQDMTTLL289 SYNRNWRVCA299 LLSCTSHKDY 309 PFHEEF
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FID or .FID2 or .FID3 or :3FID;style chemicals stick;color identity;select .A:20 or .A:47 or .A:48 or .A:79 or .A:110 or .A:111 or .A:122 or .A:219 or .A:298 or .A:299 or .A:300 or .A:301; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2PD9 Human aldose reductase mutant V47I complexed with fidarestat. | ||||||
| Method | X-ray diffraction | Resolution | 1.55 Å | Mutation | Yes | [3] |
| PDB Sequence |
ASRILLNNGA
10 KMPILGLGTW20 KSPPGQVTEA30 VKVAIDVGYR40 HIDCAHIYQN50 ENEVGVAIQE 60 KLREQVVKRE70 ELFIVSKLWC80 TYHEKGLVKG90 ACQKTLSDLK100 LDYLDLYLIH 110 WPTGFKPGKE120 FFPLDESGNV130 VPSDTNILDT140 WAAMEELVDE150 GLVKAIGISN 160 FNHLQVEMIL170 NKPGLKYKPA180 VNQIECHPYL190 TQEKLIQYCQ200 SKGIVVTAYS 210 PLGSPDRPWA220 KPEDPSLLED230 PRIKAIAAKH240 NKTTAQVLIR250 FPMQRNLVVI 260 PKSVTPERIA270 ENFKVFDFEL280 SSQDMTTLLS290 YNRNWRVCAL300 LSCTSHKDYP 310 FHEEF
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FID or .FID2 or .FID3 or :3FID;style chemicals stick;color identity;select .A:20 or .A:47 or .A:48 or .A:79 or .A:110 or .A:111 or .A:122 or .A:219 or .A:298 or .A:299 or .A:300 or .A:301; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2PDW Human aldose reductase mutant C303D complexed with fidarestat. | ||||||
| Method | X-ray diffraction | Resolution | 1.55 Å | Mutation | Yes | [3] |
| PDB Sequence |
ASRILLNNGA
10 KMPILGLGTW20 KSPPGQVTEA30 VKVAIDVGYR40 HIDCAHVYQN50 ENEVGVAIQE 60 KLREQVVKRE70 ELFIVSKLWC80 TYHEKGLVKG90 ACQKTLSDLK100 LDYLDLYLIH 110 WPTGFKPGKE120 FFPLDESGNV130 VPSDTNILDT140 WAAMEELVDE150 GLVKAIGISN 160 FNHLQVEMIL170 NKPGLKYKPA180 VNQIECHPYL190 TQEKLIQYCQ200 SKGIVVTAYS 210 PLGSPDRPWA220 KPEDPSLLED230 PRIKAIAAKH240 NKTTAQVLIR250 FPMQRNLVVI 260 PKSVTPERIA270 ENFKVFDFEL280 SSQDMTTLLS290 YNRNWRVCAL300 LSDTSHKDYP 310 FHEEF
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FID or .FID2 or .FID3 or :3FID;style chemicals stick;color identity;select .A:20 or .A:47 or .A:48 or .A:79 or .A:110 or .A:111 or .A:122 or .A:219 or .A:298 or .A:299 or .A:300 or .A:301; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2PDY Human aldose reductase double mutant S302R-C303D complexed with fidarestat. | ||||||
| Method | X-ray diffraction | Resolution | 1.65 Å | Mutation | Yes | [3] |
| PDB Sequence |
ASRILLNNGA
10 KMPILGLGTW20 KSPPGQVTEA30 VKVAIDVGYR40 HIDCAHVYQN50 ENEVGVAIQE 60 KLREQVVKRE70 ELFIVSKLWC80 TYHEKGLVKG90 ACQKTLSDLK100 LDYLDLYLIH 110 WPTGFKPGKE120 FFPLDESGNV130 VPSDTNILDT140 WAAMEELVDE150 GLVKAIGISN 160 FNHLQVEMIL170 NKPGLKYKPA180 VNQIECHPYL190 TQEKLIQYCQ200 SKGIVVTAYS 210 PLGSPDRPWA220 KPEDPSLLED230 PRIKAIAAKH240 NKTTAQVLIR250 FPMQRNLVVI 260 PKSVTPERIA270 ENFKVFDFEL280 SSQDMTTLLS290 YNRNWRVCAL300 LRDTSHKDYP 310 FHEEF
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|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FID or .FID2 or .FID3 or :3FID;style chemicals stick;color identity;select .A:20 or .A:47 or .A:48 or .A:79 or .A:110 or .A:111 or .A:122 or .A:219 or .A:298 or .A:299 or .A:300 or .A:301; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 1EF3 FIDARESTAT BOUND TO HUMAN ALDOSE REDUCTASE | ||||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [4] |
| PDB Sequence |
ASRLLLNNGA
10 KMPILGLGTW20 KSPPGQVTEA30 VKVAIDVGYR40 HIDCAHVYQN50 ENEVGVAIQE 60 KLREQVVKRE70 ELFIVSKLWC80 TYHEKGLVKG90 ACQKTLSDLK100 LDYLDLYLIH 110 WPTGFKPGKE120 FFPLDESGNV130 VPSDTNILDT140 WAAMEELVDE150 GLVKAIGISN 160 FNHLQVEMIL170 NKPGLKYKPA180 VNQIECHPYL190 TQEKLIQYCQ200 SKGIVVTAYS 210 PLGSPDRPWA220 KPEDPSLLED230 PRIKAIAAKH240 NKTTAQVLIR250 FPMQRNLVVI 260 PKSVTPERIA270 ENFKVFDFEL280 SSQDMTTLLS290 YNRNWRVCAL300 LSCTSHKDYP 310 FHEEF
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FID or .FID2 or .FID3 or :3FID;style chemicals stick;color identity;select .A:20 or .A:47 or .A:48 or .A:77 or .A:79 or .A:110 or .A:111 or .A:122 or .A:219 or .A:298 or .A:299 or .A:300; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2AGT Aldose Reductase Mutant Leu 300 Pro complexed with Fidarestat | ||||||
| Method | X-ray diffraction | Resolution | 1.00 Å | Mutation | Yes | [5] |
| PDB Sequence |
MASRILLNNG
9 AKMPILGLGT19 WKSPPGQVTE29 AVKVAIDVGY39 RHIDCAHVYQ49 NENEVGVAIQ 59 EKLREQVVKR69 EELFIVSKLW79 CTYHEKGLVK89 GACQKTLSDL99 KLDYLDLYLI 109 HWPTGFKPGK119 EFFPLDESGN129 VVPSDTNILD139 TWAAMEELVD149 EGLVKAIGIS 159 NFNHLQVEMI169 LNKPGLKYKP179 AVNQIECHPY189 LTQEKLIQYC199 QSKGIVVTAY 209 SPLGSPDRPW219 AKPEDPSLLE229 DPRIKAIAAK239 HNKTTAQVLI249 RFPMQRNLVV 259 IPKSVTPERI269 AENFKVFDFE279 LSSQDMTTLL289 SYNRNWRVCA299 PLSCTSHKDY 309 PFHEEF
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .FID or .FID2 or .FID3 or :3FID;style chemicals stick;color identity;select .A:20 or .A:47 or .A:48 or .A:79 or .A:110 or .A:111 or .A:122 or .A:219 or .A:298 or .A:299 or .A:300; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Crystal packing modifies ligand binding affinity: the case of aldose reductase. Proteins. 2012 Nov;80(11):2552-61. | ||||
| REF 2 | Ultrahigh resolution drug design. II. Atomic resolution structures of human aldose reductase holoenzyme complexed with Fidarestat and Minalrestat: implications for the binding of cyclic imide inhibitors. Proteins. 2004 Jun 1;55(4):805-13. | ||||
| REF 3 | Merging the binding sites of aldose and aldehyde reductase for detection of inhibitor selectivity-determining features. J Mol Biol. 2008 Jun 20;379(5):991-1016. | ||||
| REF 4 | A potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2', 5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (Fidarestat): its absolute configuration and interactions with the aldose reductase by X-ray crystallography. J Med Chem. 2000 Jun 15;43(12):2479-83. | ||||
| REF 5 | Factorizing selectivity determinants of inhibitor binding toward aldose and aldehyde reductases: structural and thermodynamic properties of the aldose reductase mutant Leu300Pro-fidarestat complex. J Med Chem. 2005 Sep 8;48(18):5659-65. | ||||
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