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

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...

Full description

Saved in:
Bibliographic Details
Published in:Memórias do Instituto Oswaldo Cruz 2015-04, Vol.110 (2), p.255-258
Main Authors: Guimarães, Daniel Silqueira Martins, Fonseca, Amanda Luisa da, Batista, Ronan, Junior, Moacyr Comar, Oliveira, Alaíde Braga de, Taranto, Alex Gutterres, Varotti, Fernando de Pilla
Format: Article
Language:English
Subjects:
Antimalarials - metabolism
Artemisinins - metabolism
Calcium - metabolism
Calcium-Transporting ATPases - metabolism
computer aided-drug design
Diterpenes, Kaurane - chemical synthesis
Diterpenes, Kaurane - pharmacology
Diterpenes, Kaurane - therapeutic use
docking
Drug Design
Drug Interactions
ent-kaurane diterpenes
Enzyme Inhibitors - pharmacology
malaria
Molecular Docking Simulation
Molecular Structure
PfATP6
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism
Short Communication
Thapsigargin - pharmacology
Wedelia - chemistry
Wedelia - classification
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1678-8060
0074-0276
1678-8060
DOI:10.1590/0074-02760140415