title: Targeting the fatty acid biosynthesis enzyme, beta-ketoacyl-acyl carrier protein synthase III (PfKASIII), in the identification of novel antimalarial agents.
abstract: The importance of fatty acids to the human malaria parasite, Plasmodium falciparum, and differences due to a type I fatty acid synthesis (FAS) pathway in the parasite, make it an attractive drug target. In the present study, we developed and a utilized a pharmacophore to select compounds for testing against PfKASIII, the initiating enzyme of FAS. This effort identified several PfKASIII inhibitors that grouped into various chemical classes of sulfides, sulfonamides, and sulfonyls. Approximately 60% of the submicromolar inhibitors of PfKASIII inhibited in vitro growth of the malaria parasite. These compounds inhibited both drug sensitive and resistant parasites and testing against a mammalian cell line revealed an encouraging in vitro therapeutic index for the most active compounds. Docking studies into the active site of PfKASIII suggest a potential binding mode that exploits amino acid residues at the mouth of the substrate tunnel.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Lee
authors.forename: Jayendra B
authors.initials: JB
authors.lastname: Bhonsle
authors.forename: Heather W
authors.initials: HW
authors.lastname: Gaona
authors.forename: Donald P
authors.initials: DP
authors.lastname: Huddler
authors.forename: Tiffany N
authors.initials: TN
authors.lastname: Heady
authors.forename: Mara
authors.initials: M
authors.lastname: Kreishman-Deitrick
authors.forename: Apurba
authors.initials: A
authors.lastname: Bhattacharjee
authors.forename: William F
authors.initials: WF
authors.lastname: McCalmont
authors.forename: Lucia
authors.initials: L
authors.lastname: Gerena
authors.forename: Miriam
authors.initials: M
authors.lastname: Lopez-Sanchez
authors.forename: Norma E
authors.initials: NE
authors.lastname: Roncal
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hudson
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Johnson
authors.forename: Sean T
authors.initials: ST
authors.lastname: Prigge
authors.forename: Norman C
authors.initials: NC
authors.lastname: Waters
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors*; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D003198:Computer Simulation; D005227:Fatty Acids / Q000096:biosynthesis; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; D011485:Protein Binding; D013440:Sulfides / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry; D013450:Sulfones / Q000737:chemistry
chemical_list: D000962:Antimalarials; D005227:Fatty Acids; D013440:Sulfides; D013449:Sulfonamides; D013450:Sulfones; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase