title: A plausible mechanism for the antimalarial activity of artemisinin: A computational approach.
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.
authors.affiliation: Department of Chemistry & Supercomputing Facility for Bioinformatics & Computational Biology, Indian Institute of Technology, Hauz Khas, New Delhi 110016.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Shandilya
authors.forename: Sajeev
authors.initials: S
authors.lastname: Chacko
authors.forename: B
authors.initials: B
authors.lastname: Jayaram
authors.forename: Indira
authors.initials: I
authors.lastname: Ghosh
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D037621:Artemisinins / Q000737:chemistry* / Q000494:pharmacology; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000737:chemistry / Q000378:metabolism; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps
chemical_list: C513500:ATP6 protein, Plasmodium falciparum; D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin; D007501:Iron; D000252:Calcium-Transporting ATPases; D002118:Calcium