title: Virtual fragment screening for novel inhibitors of 6-phosphogluconate dehydrogenase.
abstract: The enzyme 6-phosphogluconate dehydrogenase is a potential drug target for the parasitic protozoan Trypanosoma brucei, the causative organism of human African trypanosomiasis. This enzyme has a polar active site to accommodate the phosphate, hydroxyl and carboxylate groups of the substrate, 6-phosphogluconate. A virtual fragment screen was undertaken of the enzyme to discover starting points for the development of inhibitors which are likely to have appropriate physicochemical properties for an orally bioavailable compound. A virtual screening library was developed, consisting of compounds with functional groups that could mimic the phosphate group of the substrate, but which have a higher pKa. Following docking, hits were clustered and appropriate compounds purchased and assayed against the enzyme. Three fragments were identified that had IC50 values in the low micromolar range and good ligand efficiencies. Based on these initial hits, analogues were procured and further active compounds were identified. Some of the fragments identified represent potential starting points for a medicinal chemistry programme to develop potent drug-like inhibitors of the enzyme.
authors.affiliation: Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
authors.forename: Gian Filippo
authors.initials: GF
authors.lastname: Ruda
authors.forename: Gordon
authors.initials: G
authors.lastname: Campbell
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Alibu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010734:Phosphogluconate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D014344:Trypanocidal Agents; D010734:Phosphogluconate Dehydrogenase