title: Combined receptor-based and ligand-based approach to delineate the mode of binding of guaianolide-endoperoxides to PfATP6.
abstract: Plasmodium falciparum calcium-ATPase (PfATP6) has been reported to be a target of artemisinin and related endoperoxides. In this study, a series of previously reported guaianolide-endoperoxides (thaperoxides) were docked into a homology model of PfATP6 and also used to develop a pharmacophore model. This combined approach led to useful insights into the binding determinants of thaperoxides to the malarial enzyme. In addition, in silico mutagenesis and molecular dynamics suggested the importance of Phe264 and the electrostatic interactions between Lys260 in helix H3 and Lys1036 and Asp1038 in L6/7 loop for the binding of thaperoxides. These results could help in the design of more potent inhibitors of PfATP6.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Suez Canal University, Ismailia 41522, Egypt. mohamedahelal@gmail.com
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Helal
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D037621:Artemisinins; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D062105:Molecular Docking Simulation; D010545:Peroxides / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D045789:Sesquiterpenes, Guaiane / Q000737:chemistry* / Q000494:pharmacology*; D040681:Structural Homology, Protein
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D010545:Peroxides; D045789:Sesquiterpenes, Guaiane; C031327:artemisinin; D000252:Calcium-Transporting ATPases