Targeting multiple chorismate-utilizing enzymes with a single inhibitor: Validation of a three-stage design

Kristin T. Ziebart, Seth M. Dixon, Belem Avila, Mohamed H. El-Badri, Kathryn G. Guggenheim, Mark J. Kurth, Michael D. Toney

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Chorismate-utilizing enzymes are attractive antimicrobial drug targets due to their absence in humans and their central role in bacterial survival and virulence. The structural and mechanistic homology of a group of these inspired the goal of discovering inhibitors that target multiple enzymes. Previously, we discovered seven inhibitors of 4-amino-4-deoxychorismate synthase (ADCS) in an on-bead, fluorescent-based screen of a 2304-member one-bead-one-compound combinatorial library. The inhibitors comprise PAYLOAD and COMBI stages, which interact with active site and surface residues, respectively, and are linked by a SPACER stage. These seven compounds, and six derivatives thereof, also inhibit two other enzymes in this family, isochorismate synthase (IS) and anthranilate synthase (AS). The best binding compound inhibits ADCS, IS, and AS with K i values of 720, 56, and 80 μM, respectively. Inhibitors with varying SPACER lengths show the original choice of lysine to be optimal. Lastly, inhibition data confirm the PAYLOAD stage directs the inhibitors to the ADCS active site.

Original languageEnglish (US)
Pages (from-to)3718-3729
Number of pages12
JournalJournal of Medicinal Chemistry
Volume53
Issue number9
DOIs
StatePublished - May 13 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Ziebart, K. T., Dixon, S. M., Avila, B., El-Badri, M. H., Guggenheim, K. G., Kurth, M. J., & Toney, M. D. (2010). Targeting multiple chorismate-utilizing enzymes with a single inhibitor: Validation of a three-stage design. Journal of Medicinal Chemistry, 53(9), 3718-3729. https://doi.org/10.1021/jm100158v