Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: kinetic and structural studies

Bioorganic & Medicinal Chemistry
Marcelo S CastilhoAdriano D Andricopulo

Abstract

Selectivity plays a crucial role in the design of enzyme inhibitors as novel antiparasitic agents, particularly in cases where the target enzyme is also present in the human host. Purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive target for the discovery of potential antischistosomal agents. In the present work, kinetic studies were carried out in order to determine the inhibitory potency, mode of action and enzyme selectivity of a series of inhibitors of SmPNP. In addition, crystallographic studies provided important structural insights for rational inhibitor design, revealing consistent structural differences in the binding mode of the inhibitors in the active sites of the SmPNP and human PNP (HsPNP) structures. The molecular information gathered in this work should be useful for future medicinal chemistry efforts in the design of new inhibitors of SmPNP having increased affinity and selectivity.

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Citations

Mar 29, 2013·Analytical and Bioanalytical Chemistry·Marcela Cristina de MoraesQuezia B Cass
Jun 1, 2012·Expert Opinion on Drug Discovery·Rafaela S FerreiraGlaucius Oliva
May 23, 2015·Future Medicinal Chemistry·Leonardo G FerreiraAdriano D Andricopulo
Feb 17, 2018·Anais Da Academia Brasileira De Ciências·Leonardo G FerreiraAdriano D Andricopulo
Apr 9, 2021·Journal of Biomolecular Structure & Dynamics·Fábio José Bonfim CardosoFábio Alberto de Molfetta
Jan 30, 2018·Biochimica Et Biophysica Acta. Reviews on Cancer·Catherine J LibbyAnita B Hjelmeland
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Sep 17, 2021·The Biochemical Journal·Muhammad FaheemJoão Alexandre Ribeiro Gonçalves Barbosa

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