title: Transition-state inhibitors of purine salvage and other prospective enzyme targets in malaria.
abstract: Malaria is a leading cause of human death within the tropics. The gradual generation of drug resistance imposes an urgent need for the development of new and selective antimalarial agents. Kinetic isotope effects coupled to computational chemistry have provided the relevant details on geometry and charge of enzymatic transition states to facilitate the design of transition-state analogs. These features have been reproduced into chemically stable mimics through synthetic chemistry, generating inhibitors with dissociation constants in the pico- to femto-molar range. Transition-state analogs are expected to contribute to the control of malaria.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors.forename: Rodrigo G
authors.initials: RG
authors.lastname: Ducati
authors.forename: Hilda A
authors.initials: HA
authors.lastname: Namanja-Magliano
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
mesh_terms: D000264:Adenylosuccinate Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism
chemical_list: D000962:Antimalarials; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011687:Purines; D011759:Pyrrolidines; D013762:Tetrahydrofolate Dehydrogenase; D010430:Pentosyltransferases; C083867:hypoxanthine-guanine-xanthine phosphoribosyltransferase; D000264:Adenylosuccinate Lyase; C030985:purine