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A plausible mechanism for the antimalarial activity of artemisinin: A computational approach.

Shandilya A, Chacko S, Jayaram B, Ghosh I - Sci Rep (2013)

Bottom Line: We investigated the role of iron and artemisinin on PfATP6, in search of a plausible mechanism of action, via density functional theory calculations, docking and molecular dynamics simulations.Results suggest that artemisinin gets activated by iron which in turn inhibits PfATP6 by closing the phosphorylation, nucleotide binding and actuator domains leading to loss of function of PfATP6 of the parasite and its death.The mechanism elucidated here should help in the design of novel antimalarials.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Supercomputing Facility for Bioinformatics & Computational Biology, Indian Institute of Technology, Hauz Khas, New Delhi 110016.

ABSTRACT
Artemisinin constitutes the frontline treatment to aid rapid clearance of parasitaemia and quick resolution of malarial symptoms. However, the widespread promiscuity about its mechanism of action is baffling. There is no consensus about the biochemical target of artemisinin but recent studies implicate haem and PfATP6 (a calcium pump). We investigated the role of iron and artemisinin on PfATP6, in search of a plausible mechanism of action, via density functional theory calculations, docking and molecular dynamics simulations. Results suggest that artemisinin gets activated by iron which in turn inhibits PfATP6 by closing the phosphorylation, nucleotide binding and actuator domains leading to loss of function of PfATP6 of the parasite and its death. The mechanism elucidated here should help in the design of novel antimalarials.

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Related in: MedlinePlus

PCA based free energy landscape of open to closed conformational transition of (i) SERCA; (i) Ca2+ bound SERCA, (ii) artemisinin bound SERCA, (iii) Fe-artemisinin adduct bound SERCA.The abscissa and ordinates correspond to the first and second principal components respectively.
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f5: PCA based free energy landscape of open to closed conformational transition of (i) SERCA; (i) Ca2+ bound SERCA, (ii) artemisinin bound SERCA, (iii) Fe-artemisinin adduct bound SERCA.The abscissa and ordinates correspond to the first and second principal components respectively.

Mentions: To further understand the structural information with thermodynamics of the open to closed transition, we constructed free energy landscapes from the MD trajectories performing principal component analysis (PCA). PCA4142 uses the actual dynamics of the protein to generate the motions of the native state of the protein conformation. In Fig. 5 the energy landscape in Fe-arte-serca system reveals characteristics that are not observed either with systems serca or arte-serca. There is a well-defined minimum structurally representing the closed conformation state in Fe-arte-serca. The red region in all the plots has the least Gibbs free energy and their corresponding structures, which are most probable, are pointed with arrows.


A plausible mechanism for the antimalarial activity of artemisinin: A computational approach.

Shandilya A, Chacko S, Jayaram B, Ghosh I - Sci Rep (2013)

PCA based free energy landscape of open to closed conformational transition of (i) SERCA; (i) Ca2+ bound SERCA, (ii) artemisinin bound SERCA, (iii) Fe-artemisinin adduct bound SERCA.The abscissa and ordinates correspond to the first and second principal components respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756341&req=5

f5: PCA based free energy landscape of open to closed conformational transition of (i) SERCA; (i) Ca2+ bound SERCA, (ii) artemisinin bound SERCA, (iii) Fe-artemisinin adduct bound SERCA.The abscissa and ordinates correspond to the first and second principal components respectively.
Mentions: To further understand the structural information with thermodynamics of the open to closed transition, we constructed free energy landscapes from the MD trajectories performing principal component analysis (PCA). PCA4142 uses the actual dynamics of the protein to generate the motions of the native state of the protein conformation. In Fig. 5 the energy landscape in Fe-arte-serca system reveals characteristics that are not observed either with systems serca or arte-serca. There is a well-defined minimum structurally representing the closed conformation state in Fe-arte-serca. The red region in all the plots has the least Gibbs free energy and their corresponding structures, which are most probable, are pointed with arrows.

Bottom Line: We investigated the role of iron and artemisinin on PfATP6, in search of a plausible mechanism of action, via density functional theory calculations, docking and molecular dynamics simulations.Results suggest that artemisinin gets activated by iron which in turn inhibits PfATP6 by closing the phosphorylation, nucleotide binding and actuator domains leading to loss of function of PfATP6 of the parasite and its death.The mechanism elucidated here should help in the design of novel antimalarials.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry & Supercomputing Facility for Bioinformatics & Computational Biology, Indian Institute of Technology, Hauz Khas, New Delhi 110016.

ABSTRACT
Artemisinin constitutes the frontline treatment to aid rapid clearance of parasitaemia and quick resolution of malarial symptoms. However, the widespread promiscuity about its mechanism of action is baffling. There is no consensus about the biochemical target of artemisinin but recent studies implicate haem and PfATP6 (a calcium pump). We investigated the role of iron and artemisinin on PfATP6, in search of a plausible mechanism of action, via density functional theory calculations, docking and molecular dynamics simulations. Results suggest that artemisinin gets activated by iron which in turn inhibits PfATP6 by closing the phosphorylation, nucleotide binding and actuator domains leading to loss of function of PfATP6 of the parasite and its death. The mechanism elucidated here should help in the design of novel antimalarials.

Show MeSH
Related in: MedlinePlus