Structural bioinformatics study of PNP from Schistosoma mansoni

Area of Science:

• Parasitology and Structural Biology
• Drug Discovery and Medicinal Chemistry

Background:

• Schistosoma mansoni, a parasite causing schistosomiasis, relies on purine salvage pathways due to lacking de novo biosynthesis.
• Schistosomiasis is a major global health issue, second only to malaria in socioeconomic impact.
• Purine nucleoside phosphorylase (PNP) is a validated drug target for Schistosoma mansoni infections.

Purpose of the Study:

• To develop a structural model of Schistosoma mansoni PNP (SmPNP) complexed with inosine.
• To compare the structural and binding characteristics of SmPNP with human PNP (HsPNP).
• To correlate structural differences with observed variations in inosine binding affinity.

Main Methods:

• Homology modeling was employed using the crystal structure of human PNP-inosine complex as a template.
• The atomic coordinates of human PNP were used to build a structural model for S. mansoni PNP.
• Structural analysis focused on the complex of the modeled SmPNP with inosine.

Main Results:

• A structural model for the Schistosoma mansoni PNP-inosine complex (SmPNP-inosine) was successfully generated.
• Structural differences between SmPNP and human PNP were identified.
• These structural variations were correlated with distinct affinities for inosine binding between the two PNPs.

Conclusions:

• The generated SmPNP-inosine model provides insights into the structural basis for purine salvage in S. mansoni.
• Understanding these structural differences is crucial for the rational design of selective anti-schistosomiasis drugs targeting SmPNP.
• The study highlights the potential for structure-based drug design targeting parasitic PNP enzymes.