title: 2'-Deoxyuridine 5'-monophosphate substrate displacement in thymidylate synthase through 6-hydroxy-2H-naphtho[1,8-bc]furan-2-one derivatives.
abstract: Thymidylate synthase (TS) is a target for antifolate-based chemotherapies of microbial and human diseases. Here, ligand-based, synthetic, and X-ray crystallography studies led to the discovery of 6-(3-cyanobenzoyloxy)-2-oxo-2H-naphto[1,8-bc]furan, a novel inhibitor with a Ki of 310 nM against Pneumocystis carinii TS. The X-ray ternary complex with Escherichia coli TS revealed, for the first time, displacement of the substrate toward the dimeric protein interface, thus providing new opportunities for further design of specific inhibitors of microbial pathogens.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia , Via Campi 183, 41125 Modena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferrari
authors.forename: Samuele
authors.initials: S
authors.lastname: Calò
authors.forename: Rosalida
authors.initials: R
authors.lastname: Leone
authors.forename: Rosaria
authors.initials: R
authors.lastname: Luciani
authors.forename: Luca
authors.initials: L
authors.lastname: Costantino
authors.forename: Susan
authors.initials: S
authors.lastname: Sammak
authors.forename: Flavio
authors.initials: F
authors.lastname: Di Pisa
authors.forename: Cecilia
authors.initials: C
authors.lastname: Pozzi
authors.forename: Stefano
authors.initials: S
authors.lastname: Mangani
authors.forename: M Paola
authors.initials: MP
authors.lastname: Costi
mesh_terms: D001667:Binding, Competitive; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D062313:Databases, Pharmaceutical; D003856:Deoxyuracil Nucleotides / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D003856:Deoxyuracil Nucleotides; D004791:Enzyme Inhibitors; D005663:Furans; C007267:2'-deoxyuridylic acid; D013940:Thymidylate Synthase