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

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• 作者：Stefania Ferrari ; Samuele Cal貌 ; Rosalida Leone ; Rosaria Luciani ; Luca Costantino ; Susan Sammak ; Flavio Di Pisa ; Cecilia Pozzi ; Stefano Mangani ; M. Paola Costi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 27, 2013
• 年：2013
• 卷：56
• 期：22
• 页码：9356-9360
• 全文大小：271K
• 年卷期：v.56,no.22(November 27, 2013)
• ISSN：1520-4804

文摘

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 K_i 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.