title: Discovery of covalent inhibitors of glyceraldehyde-3-phosphate dehydrogenase, a target for the treatment of malaria.
abstract: We developed a new class of covalent inhibitors of Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase, a validated target for the treatment of malaria, by screening a small library of 3-bromo-isoxazoline derivatives that inactivate the enzyme through a covalent, selective bond to the catalytic cysteine, as demonstrated by mass spectrometry. Substituents on the isoxazolinic ring modulated the potency up to 20-fold, predominantly due to an electrostatic effect, as assessed by computational analysis.
authors.affiliation: Dipartimento di Farmacia and Centro Siteia.Parma, Università di Parma , Parco Area delle Scienze 23/A, 43124 Parma, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruno
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.forename: Gianluca
authors.initials: G
authors.lastname: Paredi
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
mesh_terms: D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013053:Spectrophotometry; D055672:Static Electricity; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D007555:Isoxazoles; D015800:Protozoan Proteins; D054852:Small Molecule Libraries; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases