2'-Deoxyuridine 5'-monophosphate substrate displacement in thymidylate synthase through 6-hydroxy-2H-naphtho[1,8-bc]furan-2-one derivatives.

Stefania Ferrari, Samuele Calò, Rosalida Leone, Rosaria Luciani, Luca Costantino, Susan Sammak, Flavio Di Pisa, Cecilia Pozzi, Stefano Mangani, M Paola Costi

Index: J. Med. Chem. 56(22) , 9356-60, (2013)

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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.