title: Novel insights into the structural requirements for the design of selective and specific aldose reductase inhibitors.
abstract: Aldose reductase (ALR2) plays a vital role in the etiology of long-term diabetic microvascular complications (DMCs) such as retinopathy, nephropathy and neuropathy. It initializes the polyol pathway and under hyperglycemic conditions, catalyzes the conversion of glucose into sorbitol in the presence of NADPH. Many ALR2 inhibitors have been withdrawn from clinical trial studies due to their cross reactivity with other analogues enzymes or due to impairment with detoxification role of ALR2. To address these issues we characterized the possible rationalities behind the selectivity problem associated with the enzyme-inhibitor interactions. Novel molecules were designed for the induce fit cavity region of ALR2. Docking studies were carried out using Glide to analyze the binding affinity of the designed molecules for ALR2. The analysis showed that the designed ALR2 inhibitors are selective for ALR2 over its close analogs. These inhibitors are also specific for the induced cavity region of ALR2 and do not interfere with the detoxification role of ALR2.
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Punjab, India.
authors.forename: Hirdesh
authors.initials: H
authors.lastname: Kumar
authors.forename: Anup
authors.initials: A
authors.lastname: Shah
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Sobhia
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D052160:Benzothiazoles / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D009249:NADP / Q000737:chemistry*; D010793:Phthalazines / Q000737:chemistry; D011485:Protein Binding; D012680:Sensitivity and Specificity
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D010793:Phthalazines; C067172:zopolrestat; D009249:NADP; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase