Linked Life Data

19121944

Source:http://linkedlifedata.com/resource/pubmed/id/19121944

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2009-2-3
pubmed:abstractText
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 IC(50) (concentration giving 50% inhibition) values of the inhibitors for the two enzymes and the binding energies (DeltaH) 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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1464-3391
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1244-50
pubmed:meshHeading
pubmed-meshheading:19121944-Aldehyde Reductase, pubmed-meshheading:19121944-Animals, pubmed-meshheading:19121944-Catalytic Domain, pubmed-meshheading:19121944-Computer Simulation, pubmed-meshheading:19121944-Crystallography, X-Ray, pubmed-meshheading:19121944-Enzyme Inhibitors, pubmed-meshheading:19121944-Humans, pubmed-meshheading:19121944-Imides, pubmed-meshheading:19121944-Inhibitory Concentration 50, pubmed-meshheading:19121944-Kinetics, pubmed-meshheading:19121944-Models, Molecular, pubmed-meshheading:19121944-Naphthalenes, pubmed-meshheading:19121944-Quercetin, pubmed-meshheading:19121944-Quinolones, pubmed-meshheading:19121944-Recombinant Proteins, pubmed-meshheading:19121944-Salicylic Acids, pubmed-meshheading:19121944-Structure-Activity Relationship, pubmed-meshheading:19121944-Swine, pubmed-meshheading:19121944-Thermodynamics
pubmed:year
2009
pubmed:articleTitle
Correlation of binding constants and molecular modelling of inhibitors in the active sites of aldose reductase and aldehyde reductase.
pubmed:affiliation
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
pubmed:publicationType
Journal Article