Identification of a novel putative inhibitor of the Plasmodium falciparum purine nucleoside phosphorylase: exploring the purine salvage pathway to design new antimalarial drugs

Molecular Diversity
Luciano Porto KagamiDaniel Fábio Kawano

Abstract

Malaria, a tropical parasitic disease caused by Plasmodium spp., continues to place a heavy social burden, with almost 200 million cases and more than 580,000 deaths per year. Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) can be targeted for antimalarial drug design since its inhibition kills malaria parasites both in vitro and in vivo. Although the currently known inhibitors of PfPNP, immucillins, are orally available and of low toxicity to animals and humans, to the best of our knowledge, none of these compounds has entered clinical trials for the treatment of malaria. Using a pharmacophore-based virtual screening coupled to a consensual molecular docking approach, we identified 59 potential PfPNP inhibitors that are predicted to be orally absorbed in a Caco-2 cell model. Although most of these compounds are predicted to have high plasma protein binding levels, poor water solubility (except for compound 25) and CYP3A4 metabolic stability (except for 4, 7 and 8), four structures (4, 7, 8 and 25) remain as potential leads because of their plausible interaction with a specific hydrophobic pocket of PfPNP, which would confer them higher selectivity for PfPNP over human PNP. Additionally, both predicted Gibbs free ...Continue Reading

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Citations

Aug 2, 2018·Molecular Informatics·Alexandre BorgesRosangela da Silva de Laurentiz
Oct 20, 2018·Chemistry & Biodiversity·Renato L T ParreiraMárcio L Andrade E Silva
Apr 9, 2020·Frontiers in Cellular and Infection Microbiology·Congshan LiuHaobing Zhang
Oct 20, 2020·International Journal of Biological Macromolecules·Rudson J HolandaLuiz H Pereira da Silva
Sep 19, 2020·Journal of Molecular Graphics & Modelling·Maycon D de OliveiraAnderson H Lima
Jun 16, 2021·Journal of Biomolecular Structure & Dynamics·Vivek K VyasManjunath Ghate

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Astex Statistical Potential ( ASP
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Discovery Studio Visualizer
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Molecular Discovery VolSurf Plus
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