title: Discovery of new selective human aldose reductase inhibitors through virtual screening multiple binding pocket conformations.
abstract: Aldose reductase reduces glucose to sorbitol. It plays a key role in many of the complications arising from diabetes. Thus, aldose reductase inhibitors (ARI) have been identified as promising therapeutic agents for treating such complications of diabetes, as neuropathy, nephropathy, retinopathy, and cataracts. In this paper, a virtual screening protocol applied to a library of compounds in house has been utilized to discover novel ARIs. IC50's were determined for 15 hits that inhibited ALR2 to greater than 50% at 50 μM, and ten of these have an IC50 of 10 μM or less, corresponding to a rather substantial hit rate of 14% at this level. The specificity of these compounds relative to their cross-reactivity with human ALR1 was also assessed by inhibition assays. This resulted in identification of novel inhibitors with IC50's comparable to the commercially available drug, epalrestat, and greater than an order of magnitude better selectivity.
authors.affiliation: Research Center for Drug Discovery & Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gu
authors.forename: Xuehua
authors.initials: X
authors.lastname: Zheng
authors.forename: Jiming
authors.initials: J
authors.lastname: Ye
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
authors.forename: Jiabo
authors.initials: J
authors.lastname: Li
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Hu
authors.forename: Arnold
authors.initials: A
authors.lastname: Hagler
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D000449:Aldehyde Reductase