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

摘要: To identify specific bacterial thymidylate synthase (TS) inhibitors, we exploited phenolphthalein (PTH), which inhibits both and human enzymes. The X-ray crystal structure of Lactobacillus casei TS (LcTS) that binds PTH showed multiple binding modes the inhibitor, prevented a classical structure-based drug design approach. overcome this issue, synthesized two phthalimidic libraries were tested against enzymes then performed crystallographic screening active compounds. Compounds 6A, 8A, 12A 40-fold higher affinity for than TS. characterized mode six inhibitors in complexes with LcTS. Of these, 20A, 23A, 24A common unique mode, whereas 8A different, mode. A comparative analysis LcTS obtained pathogenic enabled selection compounds 23A as starting points to be inhibition pathogen