Crystallographic approach to fragment-based hit discovery against Schistosoma mansoni purine nucleoside

Several Schistosoma species cause Schistosomiasis, an endemic disease in 78 countries that is ranked second amongst the parasitic diseases in terms of its socioeconomic impact and human health importance. The drug recommended for treatment by the is praziquantel (PZQ), but there are concerns associated with PZQ, such as the information about its exact mechanism of action, its high price, its effectiveness - is limited to the parasite's adult form - and reports of resistance. The parasites lack de novo purine pathway, rendering them dependent on the purine salvage pathway host purine bases for nucleotide synthesis. Thus, the Schistosoma purine salvage pathway is an attractive target for the development of necessary and selective drugs. In this study, the purine nucleotide phosphorylase II (PNP2), a new isoform PNP1, was submitted to a high-throughput fragment-based hit discovery using a crystallographic screening strategy. PNP2 was crystallized and crystals were soaked with fragments, a subset of the Maybridge 1000 library. X-ray diffraction data was collected and structures were solved. Out of 827-screened fragments we have obtained a total 19 fragments that show binding to PNP2. Fourteen of these fragments bind to the