Abstract
The enzyme purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive molecular target for the development of novel drugs against schistosomiasis, a neglected tropical disease that affects about 200 million people worldwide. In the present work, enzyme kinetic studies were carried out in order to determine the potency and mechanism of inhibition of a series of SmPNP inhibitors. In addition to the biochemical investigations, crystallographic and molecular modeling studies revealed important molecular features for binding affinity towards the target enzyme, leading to the development of structure-activity relationships (SAR).
Highlights
Neglected tropical diseases are responsible for millions of deaths and disabilities every year
Considering the key role of PNP in the purine salvage pathway of the S. mansoni parasite, this enzyme has been selected as a potential target for the chemotherapeutic treatment of schistosomiasis
The difference of about 6-fold in the KM (MichaelisMenten constant) values between human and parasite PNPs for the natural substrate indicates that binding affinity depends on specific molecular interactions between smallmolecule ligand and protein
Summary
Neglected tropical diseases are responsible for millions of deaths and disabilities every year. We have evaluated a series of guanine derivatives against SmPNP in order to determine their in vitro potency, affinity and mechanism of inhibition.
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