Identification of the binding modes of N-phenylphthalimides inhibiting bacterial thymidylate synthase through X-ray crystallography screening

S Mangani, L Cancian, R Leone, C Pozzi…

Index: Mangani, Stefano; Cancian, Laura; Leone, Rosalida; Pozzi, Cecilia; Lazzari, Sandra; Luciani, Rosaria; Ferrari, Stefania; Costi, M. Paola Journal of Medicinal Chemistry, 2011 , vol. 54, # 15 p. 5454 - 5467

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Citation Number: 6

Abstract

To identify specific bacterial thymidylate synthase (TS) inhibitors, we exploited phenolphthalein (PTH), which inhibits both bacterial and human enzymes. The X-ray crystal structure of Lactobacillus casei TS (LcTS) that binds PTH showed multiple binding modes of the inhibitor, which prevented a classical structure-based drug design approach. To overcome this issue, we synthesized two phthalimidic libraries that were tested against TS ...