title: Virtual screening for inhibitors of human aldose reductase.
abstract: The inhibition of aldose reductase (AR) provides an interesting strategy to prevent the complications of chronic diabetes. Although a large number of different AR inhibitors are known, very few of these compounds exhibit sufficient efficacy in clinical trials. We performed a virtual screening based on the ultrahigh resolution crystal structure of the inhibitor IDD594 in complex with human AR. AR operates on a large scale of structurally different substrates. To achieve this pronounced promiscuity, the enzyme can adapt rather flexibly to its substrates. Likewise, it has a similar adaptability for the binding of inhibitors. We applied a protocol of consecutive hierarchical filters to search the Available Chemicals Directory. In the first selection step, putative ligands were chosen that exhibit functional groups to anchor the anion-binding pocket of AR. Subsequently, a pharmacophore model based on the binding geometry of IDD594 and the mapping of the binding pocket in terms of putative "hot spots" of binding was applied as a second consecutive filter. In a third and final filtering step, the remaining candidate molecules were flexibly docked into the binding pocket of IDD594 with FlexX and ranked according to their estimated DrugScore values. Out of 206 compounds selected by this search and complemented by a cluster analysis and visual inspection, 9 compounds were selected and subjected to biological testing. Of these, 6 compounds showed IC50 values in the micromolar range. According to the proposed binding mode, the two inhibitors BTB02809 (IC50 = 2.4 +/- 0.5 microM) and JFD00882 (IC50 = 4.1 +/- 1.0 microM) both place a nitro group into the hydrophobic specificity pocket of human AR in an orientation coinciding with the position of the bromine atom of IDD594. The interaction of this Br with Thr113 has been identified as a key feature that is responsible for selectivity enhancement.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kraemer
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hazemann
authors.forename: Alberto D
authors.initials: AD
authors.lastname: Podjarny
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000378:metabolism; D000449:Aldehyde Reductase / Q000737:chemistry* / Q000378:metabolism; D000838:Anions / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding; D013854:Thioamides; D013859:Thiocarbamates / Q000737:chemistry / Q000378:metabolism
chemical_list: D000085:Acetates; D000838:Anions; D004791:Enzyme Inhibitors; C487992:Idd 594; D013854:Thioamides; D013859:Thiocarbamates; D000449:Aldehyde Reductase