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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

Interaction network of Fe-artemisinin adduct and phosphorylation site through bonded and non-bonded network.(a) A three dimensional view; (b) A two dimensional representation of the same linkage.
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f6: Interaction network of Fe-artemisinin adduct and phosphorylation site through bonded and non-bonded network.(a) A three dimensional view; (b) A two dimensional representation of the same linkage.

Mentions: A key question is how the ligand binding site and the phosphorylation site, 25Å apart, communicate with each other. In this regard, it is important to note that the cytoplasmic end of M5 is integrated into the P-domain near the phosphorylation site and hydrogen bonded to the M4 helix. We analyzed the hydrogen bond linkage from the simulation trajectory of Fe-arte-serca system. There is an apparent linkage of network between Fe-artemisinin adduct and SER 357 (phosphorylation site) which plays a pivotal role in the functioning of SERCA. Also, SER 357 is directly connected to the nucleotide domain through a loop. Fe-artemisinin adduct makes hydrogen bond with ASN 1039 which is connected to SER 357 (phosphorylation site) through hydrogen bonds, loop region and sheets. (Fig. 6). A tilt and lateral shift of M5 which leads to the large movement of nucleotide domain can also be attributed to the analogous linkage of Fe-artemisinin adduct with ILE 977 mentioned earlier. Main chain and H-bond connectivity are shown in Fig. 6a. Residue ASN 951, at one terminal of the M5 helix shows strong interaction with THR 362 of phosphorylation domain, thus directly modulating the motion of the nucleotide domain. In addition to this, interaction of Fe-artemisinin adduct and residues of M4 (ASN 1039 and loop) helix also strongly influence the movement of the nucleotide domain. A network of hydrogen bonds between Fe-artemisinin adduct, LEU 263 and LYS 259, attached to the actuator domain through a loop, regulates the motion of the actuator domain as shown in Fig. 6b. There are other networks of ASP 358 alongside M5 and M4 where Fe-artemisinin adduct is located. However, the interactions mentioned above were found to be stronger indicated by a high survival of hydrogen bonds throughout the trajectory (almost 70% of the simulation run time taking hydrogen bond distance cut off as 3.2 Å). These hydrogen bond linkages were not found with artemisinin bound complex during the simulation (supplementary Fig. S13). It is quite probable that many H-bond networks amongst P domain and the M5 and M4 helices in association with other sites (Fig. 6) are responsible for the allosteric effect between the ligand binding site and the cytosolic regions, causing the closure of two domains leading to inaccessibility of calcium ion at the calcium binding site. Thus, the events that occur at either site can be mechanically transmitted to the other site.


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

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

Interaction network of Fe-artemisinin adduct and phosphorylation site through bonded and non-bonded network.(a) A three dimensional view; (b) A two dimensional representation of the same linkage.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Interaction network of Fe-artemisinin adduct and phosphorylation site through bonded and non-bonded network.(a) A three dimensional view; (b) A two dimensional representation of the same linkage.
Mentions: A key question is how the ligand binding site and the phosphorylation site, 25Å apart, communicate with each other. In this regard, it is important to note that the cytoplasmic end of M5 is integrated into the P-domain near the phosphorylation site and hydrogen bonded to the M4 helix. We analyzed the hydrogen bond linkage from the simulation trajectory of Fe-arte-serca system. There is an apparent linkage of network between Fe-artemisinin adduct and SER 357 (phosphorylation site) which plays a pivotal role in the functioning of SERCA. Also, SER 357 is directly connected to the nucleotide domain through a loop. Fe-artemisinin adduct makes hydrogen bond with ASN 1039 which is connected to SER 357 (phosphorylation site) through hydrogen bonds, loop region and sheets. (Fig. 6). A tilt and lateral shift of M5 which leads to the large movement of nucleotide domain can also be attributed to the analogous linkage of Fe-artemisinin adduct with ILE 977 mentioned earlier. Main chain and H-bond connectivity are shown in Fig. 6a. Residue ASN 951, at one terminal of the M5 helix shows strong interaction with THR 362 of phosphorylation domain, thus directly modulating the motion of the nucleotide domain. In addition to this, interaction of Fe-artemisinin adduct and residues of M4 (ASN 1039 and loop) helix also strongly influence the movement of the nucleotide domain. A network of hydrogen bonds between Fe-artemisinin adduct, LEU 263 and LYS 259, attached to the actuator domain through a loop, regulates the motion of the actuator domain as shown in Fig. 6b. There are other networks of ASP 358 alongside M5 and M4 where Fe-artemisinin adduct is located. However, the interactions mentioned above were found to be stronger indicated by a high survival of hydrogen bonds throughout the trajectory (almost 70% of the simulation run time taking hydrogen bond distance cut off as 3.2 Å). These hydrogen bond linkages were not found with artemisinin bound complex during the simulation (supplementary Fig. S13). It is quite probable that many H-bond networks amongst P domain and the M5 and M4 helices in association with other sites (Fig. 6) are responsible for the allosteric effect between the ligand binding site and the cytosolic regions, causing the closure of two domains leading to inaccessibility of calcium ion at the calcium binding site. Thus, the events that occur at either site can be mechanically transmitted to the other site.

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