Structure-based drug design studies of the interactions of ent-kaurane diterpenes derived from Wedelia paludosa with the Plasmodium falciparum sarco/endoplasmic reticulum Ca²⁺-ATPase PfATP6.

Daniel Silqueira Martins Guimarães,Alex Gutterres Taranto,Ronan Batista,Alaíde Braga De Oliveira,Fernando De Pilla Varotti,Amanda Luisa Da Fonseca,Moacyr Comar Junior

doi:10.1590/0074-02760140415

Abstract

Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosa were tested in silico against the Plasmodium falciparum Ca2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.

Highlights

Malaria is the most widespread infectious parasitic disease around the world (WHO 2013)
Among the numerous genes involved in artemisinin resistance, PfATP6, a sarco/endoplasmic reticulum Ca2+ATPase (SERCA) homologue expressed in Plasmodium falciparum, has been suggested as a possible target of artemisinin (Valderramos et al 2010, Cui et al 2012)
Financial support: FAPEMIG, CNPq + Corresponding author: varotti@ufsj.edu.br Received 4 November 2014 Accepted 29 January 2015 al. 2014) we investigated the interaction between the entkaurane diterpenes and PfATP6 (Gardner et al 2002)

Summary

Introduction

Malaria is the most widespread infectious parasitic disease around the world (WHO 2013). Due to the selective antimalarial activity exhibited by these compounds and knowing that diterpenes induce calcium overload in myocytes Molecular mechanisms that maintain parasite calcium homeostasis are controlled by proteins such as PfATP6 (Krishna et al 2010).

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