title: Exploring DOXP-reductoisomerase binding limits using phosphonated N-aryl and N-heteroarylcarboxamides as DXR inhibitors.
abstract: DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand-receptor interactions.
authors.affiliation: Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown 6140, South Africa.
authors.forename: Taryn
authors.initials: T
authors.lastname: Bodill
authors.forename: Anne C
authors.initials: AC
authors.lastname: Conibear
authors.forename: Marius K M
authors.initials: MK
authors.lastname: Mutorwa
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Goble
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Blatch
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Lobb
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Klein
authors.forename: Perry T
authors.initials: PT
authors.lastname: Kaye
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects
chemical_list: D000577:Amides; D002219:Carbamates; D004791:Enzyme Inhibitors; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases; C070766:carbamic acid