Discovery of inhibitors of lupin diadenosine 5′,5‴-P 1,P4-tetraphosphate hydrolase by virtual screening

Abstract

Novel inhibitors of lupin diadenosine 5′,5‴-P 1,P4-tetraphosphate (Ap4A) 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 Ki of 1 μM. A stru..