Tropical diseases are a major focus of special research programs in the World Health Organization. One of such diseases is Schistosomiasis, which affects about 300 million people around the World. Among all species of Schistosomas, the only found in Brazil is Schistosoma mansoni. The lack of more effective and safe treatments for schistosomiasis has been stimulating the search for new attractive biological targets as well as promising molecules for drug research. Enzyme inhibitors play a crucial role in the pharmaceutical industry. Parasite enzymes are attractive targets for drug discovery. The enzyme purine nucleoside phosphorylase (PNP, EC 2.4.2.1) from Schistosoma mansoni is an important target for the development of new chemotherapeutic agents. In presented work, we describe the results of the development of structure-activity relationships (SAR) for a set of inhibitors of S. mansoni PNP. The family of 10 PNP inhibitors examined is 9-substituted-9-deazaguanines. The bulk of the structural diversity lies in the nature of the substituent linked to the 9-position of the purine ring. IC₅₀ values were measured employing inosine as substrate and a UV spectrophotometric assay, by varying the inhibitor concentration at fixed substrate and enzyme concentrations. Molecular modeling studies were carried out using the docking programs GOLD and FlexX. All docking simulations were carried out with the X-ray coordinates of S. mansoni PNP (available in our laboratories) to which hydrogen atoms were added in standard geometry, after removal of the ligand and water molecules. SAR studies revealed the essential interactions between the PNP active site and small-molecule inhibitors. These studies have identified the key residues in PNP catalytic mechanism, where the carboxamide group of the Asn245 side chain forms a hydrogen bond with O6 of the purine ring, while the side-chain carboxylate of Glu203 is close to accepting a hydrogen bond from N1. According to the proposed binding model developed, additional molecular modifications can be proposed for the synthesis of more potent and selective inhibitors of PNP from S. mansoni.