Virtual fragment screening for novel inhibitors of 6-phosphogluconate dehydrogenase

Ruda, G. F., Campbell, G., Alibu, V. P., Barrett, M.P. , Brenk, R. and Gilbert, I. H. (2010) Virtual fragment screening for novel inhibitors of 6-phosphogluconate dehydrogenase. Bioorganic and Medicinal Chemistry, 18(14), pp. 5056-5062. (doi:10.1016/j.bmc.2010.05.077)

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Publisher's URL: http://dx.doi.org/10.1016/j.bmc.2010.05.077

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

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Barrett, Professor Michael
Authors: Ruda, G. F., Campbell, G., Alibu, V. P., Barrett, M.P., Brenk, R., and Gilbert, I. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Bioorganic and Medicinal Chemistry
ISSN:0968-0896
Published Online:09 June 2010

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
386141Inhibitors of trypanosomal 6-phosphogluconate dehydrogenase - modes of action and drug delivery strategiesMichael BarrettWellcome Trust (WELLCOME)075277/A/04/ZInfection Immunity and Inflammation Life Sciences