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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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MD snapshots generated from individual trajectories after every 25 ns for PfATP6 enzyme (top row), artemisinin bound PfATP6 (second row) and Fe-artemisinin adduct bound PfATP6 (third row).Nucleotide binding (N) domain and the actuator (A) domains are seen to be closing in the case of Fe-artemisinin adduct bound PfATP6 system.
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f2: MD snapshots generated from individual trajectories after every 25 ns for PfATP6 enzyme (top row), artemisinin bound PfATP6 (second row) and Fe-artemisinin adduct bound PfATP6 (third row).Nucleotide binding (N) domain and the actuator (A) domains are seen to be closing in the case of Fe-artemisinin adduct bound PfATP6 system.

Mentions: The essential massage of molecular dynamics (MD) simulations are captured in Fig. 2 in which systems (i) and (ii) viz. PfATP6 and artemisinin-PfATP6 complex show no major conformational changes. The two domains N & A, remain (~25Å) away from each other as in the native structure. However, they exhibit significant local fluctuations and some rearrangements. System (iii) namely, Fe-artemisinin adduct bound to PfATP6 shows a dramatic large conformational change resulting in a closure of N- and A- domains (see Fig. 2 and supplementary Fig. S5). Systerm (iv) too, namely thapsigargin bound to mammalian SERCA shows a similar large conformational change consistent with the experiment37 (also see supplementary Fig. S6 and S7).


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

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

MD snapshots generated from individual trajectories after every 25 ns for PfATP6 enzyme (top row), artemisinin bound PfATP6 (second row) and Fe-artemisinin adduct bound PfATP6 (third row).Nucleotide binding (N) domain and the actuator (A) domains are seen to be closing in the case of Fe-artemisinin adduct bound PfATP6 system.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: MD snapshots generated from individual trajectories after every 25 ns for PfATP6 enzyme (top row), artemisinin bound PfATP6 (second row) and Fe-artemisinin adduct bound PfATP6 (third row).Nucleotide binding (N) domain and the actuator (A) domains are seen to be closing in the case of Fe-artemisinin adduct bound PfATP6 system.
Mentions: The essential massage of molecular dynamics (MD) simulations are captured in Fig. 2 in which systems (i) and (ii) viz. PfATP6 and artemisinin-PfATP6 complex show no major conformational changes. The two domains N & A, remain (~25Å) away from each other as in the native structure. However, they exhibit significant local fluctuations and some rearrangements. System (iii) namely, Fe-artemisinin adduct bound to PfATP6 shows a dramatic large conformational change resulting in a closure of N- and A- domains (see Fig. 2 and supplementary Fig. S5). Systerm (iv) too, namely thapsigargin bound to mammalian SERCA shows a similar large conformational change consistent with the experiment37 (also see supplementary Fig. S6 and S7).

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