QSAR-Driven design and discovery of novel compounds with antiplasmodial and transmission blocking activities
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2018
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Resumo
Malaria is a life-threatening infectious disease caused by parasites of the genus
Plasmodium, affecting more than 200 million people worldwide every year and leading
to about a half million deaths. Malaria parasites of humans have evolved resistance
to all current antimalarial drugs, urging for the discovery of new effective compounds.
Given that the inhibition of deoxyuridine triphosphatase of Plasmodium falciparum
(PfdUTPase) induces wrong insertions in plasmodial DNA and consequently leading
the parasite to death, this enzyme is considered an attractive antimalarial drug target.
Using a combi-QSAR (quantitative structure-activity relationship) approach followed by
virtual screening and in vitro experimental evaluation, we report herein the discovery
of novel chemical scaffolds with in vitro potency against asexual blood stages of
both P. falciparum multidrug-resistant and sensitive strains and against sporogonic
development of P. berghei. We developed 2D- and 3D-QSAR models using a series
of nucleosides reported in the literature as PfdUTPase inhibitors. The best models
were combined in a consensus approach and used for virtual screening of the
ChemBridge database, leading to the identification of five new virtual PfdUTPase
inhibitors. Further in vitro testing on P. falciparum multidrug-resistant (W2) and sensitive
(3D7) parasites showed that compounds LabMol-144 and LabMol-146 demonstrated
fair activity against both strains and presented good selectivity versus mammalian cells.
In addition, LabMol-144 showed good in vitro inhibition of P. berghei ookinete formation,
demonstrating that hit-to-lead optimization based on this compound may also lead to
new antimalarials with transmission blocking activity.
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Malaria, Virtual screening, QSAR, Plasmodium falciparum, dUTPase, Transmission blocker
Citação
LIMA, Marilia. N. N. et al. QSAR-Driven design and discovery of novel compounds with antiplasmodial and transmission blocking activities. Frontiers in Pharmacology, Lausanne, v. 9, e146, 2018. DOI: 10.3389/fphar.2018.00146. Disponível em: https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00146/full. Acesso em: 8 nov. 2024.