Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1244 - 1250 |
| Number of pages | 7 |
| Journal | Bioorganic & Medicinal Chemistry |
| Volume | 17 |
| Issue number | 3 |
| Publication status | Published - 2009 |
Cite this
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Correlation of binding constants and molecular modelling of inhibitors in the active sites of aldose reductase and aldehyde reductase. / Carbone, Vincenzo; Zhao, Hai-Tao; Chung, Roland Poh-Tuck; Endo, Satoshi; Hara, Akira; El-Kabbani, Ossama.
In: Bioorganic & Medicinal Chemistry, Vol. 17, No. 3, 2009, p. 1244 - 1250.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Correlation of binding constants and molecular modelling of inhibitors in the active sites of aldose reductase and aldehyde reductase
AU - Carbone, Vincenzo
AU - Zhao, Hai-Tao
AU - Chung, Roland Poh-Tuck
AU - Endo, Satoshi
AU - Hara, Akira
AU - El-Kabbani, Ossama
PY - 2009
Y1 - 2009
N2 - Aldose reductase (ALR2) belongs to the aldo-keto reductase ( AKR) superfamily of enzymes, is the first enzyme involved in the polyol pathway of glucose metabolism and has been linked to the pathologies associated with diabetes. Molecular modelling studies together with binding constant measurements for the four inhibitors Tolrestat, Minalrestat, quercetin and 3,5-dichlorosalicylic acid (DCL) were used to determine the type of inhibition, and correlate inhibitor potency and binding energies of the complexes with ALR2 and the homologous aldehyde reductase (ALR1), another member of the AKR superfamily. Our results show that the four inhibitors follow either uncompetitive or non-competitive inhibition pattern of substrate reduction for ALR1 and ALR2. Overall, there is correlation between the IC50 ( concentration giving 50 inhibition) values of the inhibitors for the two enzymes and the binding energies (Delta H) of the enzyme-inhibitor complexes. Additionally, the results agree with the detailed structural information obtained by X-ray crystallography suggesting that the difference in inhibitor binding for the two enzymes is predominantly mediated by non-conserved residues. In particular, Arg312 in ALR1 ( missing in ALR2) contributes favourably to the binding of DCL through an electrostatic interaction with the inhibitor s electronegative halide atom and undergoes a conformational change upon Tolrestat binding. In ALR2, Thr113 ( Tyr116 in ALR1) forms electrostatic interactions with the. fluorobenzyl moiety of Minalrestat and the 3- and 4-hydroxy groups on the phenyl ring of quercetin. Our modelling studies suggest that Minalrestat s binding to ALR1 is accompanied by a conformational change including the side chain of Tyr116 to achieve the selectivity for ALR1 over ALR2. (c) 2008 Elsevier Ltd. All rights reserved.
AB - Aldose reductase (ALR2) belongs to the aldo-keto reductase ( AKR) superfamily of enzymes, is the first enzyme involved in the polyol pathway of glucose metabolism and has been linked to the pathologies associated with diabetes. Molecular modelling studies together with binding constant measurements for the four inhibitors Tolrestat, Minalrestat, quercetin and 3,5-dichlorosalicylic acid (DCL) were used to determine the type of inhibition, and correlate inhibitor potency and binding energies of the complexes with ALR2 and the homologous aldehyde reductase (ALR1), another member of the AKR superfamily. Our results show that the four inhibitors follow either uncompetitive or non-competitive inhibition pattern of substrate reduction for ALR1 and ALR2. Overall, there is correlation between the IC50 ( concentration giving 50 inhibition) values of the inhibitors for the two enzymes and the binding energies (Delta H) of the enzyme-inhibitor complexes. Additionally, the results agree with the detailed structural information obtained by X-ray crystallography suggesting that the difference in inhibitor binding for the two enzymes is predominantly mediated by non-conserved residues. In particular, Arg312 in ALR1 ( missing in ALR2) contributes favourably to the binding of DCL through an electrostatic interaction with the inhibitor s electronegative halide atom and undergoes a conformational change upon Tolrestat binding. In ALR2, Thr113 ( Tyr116 in ALR1) forms electrostatic interactions with the. fluorobenzyl moiety of Minalrestat and the 3- and 4-hydroxy groups on the phenyl ring of quercetin. Our modelling studies suggest that Minalrestat s binding to ALR1 is accompanied by a conformational change including the side chain of Tyr116 to achieve the selectivity for ALR1 over ALR2. (c) 2008 Elsevier Ltd. All rights reserved.
UR - http://www.sciencedirect.com.ezproxy.lib.monash.edu.au/science?_ob=ArticleURL&_udi=B6TF8-4V70R7V-3&_user=542840&_coverDate=02%2F01%2F2009&_rdoc=1&_fmt
M3 - Article
VL - 17
SP - 1244
EP - 1250
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 3
ER -