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.

2′-Deoxyuridine 5′-Monophosphate Substrate Displacement in Thymidylate Synthase through 6-Hydroxy-2H-naphtho[1,8-bc]furan-2-one Derivatives / Ferrari, Stefania; Calò, S; Leone, R; Luciani, Rosaria; Costantino, Luca; Sammak, Susan; Di Pisa, F; Pozzi, C; Mangani, S; Costi, Maria Paola. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:22(2013), pp. 9356-9360. [10.1021/jm4014086]

2′-Deoxyuridine 5′-Monophosphate Substrate Displacement in Thymidylate Synthase through 6-Hydroxy-2H-naphtho[1,8-bc]furan-2-one Derivatives

FERRARI, Stefania;LUCIANI, Rosaria;COSTANTINO, Luca;SAMMAK, SUSAN;COSTI, Maria Paola
2013

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.
2013
56
22
9356
9360
2′-Deoxyuridine 5′-Monophosphate Substrate Displacement in Thymidylate Synthase through 6-Hydroxy-2H-naphtho[1,8-bc]furan-2-one Derivatives / Ferrari, Stefania; Calò, S; Leone, R; Luciani, Rosaria; Costantino, Luca; Sammak, Susan; Di Pisa, F; Pozzi, C; Mangani, S; Costi, Maria Paola. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:22(2013), pp. 9356-9360. [10.1021/jm4014086]
Ferrari, Stefania; Calò, S; Leone, R; Luciani, Rosaria; Costantino, Luca; Sammak, Susan; Di Pisa, F; Pozzi, C; Mangani, S; Costi, Maria Paola
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1004516
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