title: 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.
abstract: 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.
authors.affiliation: Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João del-Rei, Divinópolis, MG, Brasil.
authors.forename: Daniel Silqueira Martins
authors.initials: DS
authors.lastname: Guimarães
authors.affiliation: Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João del-Rei, Divinópolis, MG, Brasil.
authors.forename: Amanda Luisa da
authors.initials: AL
authors.lastname: Fonseca
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, Universidade Federal da Bahia, Salvador, BA, Brasil.
authors.forename: Ronan
authors.initials: R
authors.lastname: Batista
authors.affiliation: Laboratório de Modelagem Molecular, Universidade Federal de São João del-Rei, Divinópolis, MG, Brasil.
authors.forename: Moacyr
authors.initials: M
authors.lastname: Comar Junior
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil.
authors.forename: Alaíde Braga de
authors.initials: AB
authors.lastname: Oliveira
authors.affiliation: Laboratório de Química Farmacêutica Medicinal, Universidade Federal de São João del-Rei, Divinópolis, MG, Brasil.
authors.forename: Alex Gutterres
authors.initials: AG
authors.lastname: Taranto
authors.affiliation: Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João del-Rei, Divinópolis, MG, Brasil.
authors.forename: Fernando de Pilla
authors.initials: Fde P
authors.lastname: Varotti
mesh_terms: D000962:Antimalarials / Q000378:metabolism; D037621:Artemisinins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D045786:Diterpenes, Kaurane / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D031209:Wedelia / Q000737:chemistry* / Q000145:classification
chemical_list: C513500:ATP6 protein, Plasmodium falciparum; D000962:Antimalarials; D037621:Artemisinins; D045786:Diterpenes, Kaurane; D004791:Enzyme Inhibitors; D019284:Thapsigargin; C031327:artemisinin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium