1. Discovery of inhibitors of lupin diadenosine 5',5'''-P(1),P(4)-tetraphosphate hydrolase by virtual screening.
- Author
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Branson KM, Mertens HD, Swarbrick JD, Fletcher JI, Kedzierski L, Gayler KR, Gooley PR, and Smith BJ
- Subjects
- Acid Anhydride Hydrolases chemistry, Acid Anhydride Hydrolases genetics, Animals, Calorimetry, Catalytic Domain, Computer Simulation, Dinucleoside Phosphates chemistry, Dinucleoside Phosphates metabolism, Drug Discovery, Enzyme Inhibitors pharmacology, Fibroblasts drug effects, Humans, Isoenzymes antagonists & inhibitors, Isoenzymes chemistry, Isoenzymes genetics, Isoenzymes metabolism, Models, Molecular, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Plant Proteins chemistry, Plant Proteins genetics, Platelet Aggregation Inhibitors chemistry, Platelet Aggregation Inhibitors metabolism, Protein Conformation, Acid Anhydride Hydrolases antagonists & inhibitors, Acid Anhydride Hydrolases metabolism, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Lupinus enzymology, Plant Proteins antagonists & inhibitors, Plant Proteins metabolism
- Abstract
Novel inhibitors of lupin diadenosine 5',5'''-P(1),P(4)-tetraphosphate (Ap(4)A) hydrolase have been identified by in silico screening of a large virtual chemical library. Compounds were ranked on the basis of a consensus from six scoring functions. From the top 100 ranked compounds six were selected and initially screened for inhibitory activity using a single concentration isothermal titration calorimetry assay. Two of these compounds that showed excellent solubility properties were further analyzed, but only one [NSC51531; 2-((8-hydroxy-4-(4-methyl-2-sulfoanilino)-9,10-dioxo-9,10-dihydro-1-anthracenyl)amino)-5-methylbenzenesulfonic acid] exhibited competitive inhibition with a K(i) of 1 microM. A structural analogue of this compound also exhibited competitive inhibition with a comparable K(i) of 2.9 microM. (1)H, (15)N NMR spectroscopy was used to map the binding site of NSC51531 on lupin Ap(4)A hydrolase and demonstrated that the compound bound specifically in the substrate-binding site, consistent with the competitive inhibition results. Binding of NSC51531 to the human form of Ap(4)A hydrolase is nonspecific, suggesting that this compound may represent a useful lead in the design of specific inhibitors of the plant-like form of Ap(4)A hydrolases.
- Published
- 2009
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