Aminodeoxychorismate synthase inhibitors from one-bead one-compound combinatorial libraries: "Staged" inhibitor design

Seth Dixon, Kristin T. Ziebart, Ze He, Melissa Jeddeloh, Choong Leol Yoo, Xiaobing Wang, Alan Lehman, Kit Lam, Michael D. Toney, Mark J. Kurth

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

4-Amino-4-deoxychorismate synthase (ADCS) catalyzes the first step in the conversion of chorismate into p-aminobenzoate, which is incorporated into folic acid. We aim to discover compounds that inhibit ADCS and serve as leads for a new class of antimicrobial compounds. This report presents (1) synthesis of a mass-tag encoded library based on a "staged" design, (2) massively parallel fluorescence-based on-bead screening, (3) rapid structural identification of hits, and (4) full kinetic analysis of ADCS. All inhibitors are competitive against chorismate and Mg2+. The most potent ADCS inhibitor identified has a Ki of 360 μM. We show that the combinatorial diversity elements add substantial binding affinity by interacting with residues outside of but proximal to the active site. The methods presented here constitute a paradigm for inhibitor discovery through active site targeting, enabled by rapid library synthesis, facile massively parallel screening, and straightforward hit identification.

Original languageEnglish (US)
Pages (from-to)7413-7426
Number of pages14
JournalJournal of Medicinal Chemistry
Volume49
Issue number25
DOIs
StatePublished - Dec 14 2006

ASJC Scopus subject areas

  • Organic Chemistry

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    Dixon, S., Ziebart, K. T., He, Z., Jeddeloh, M., Yoo, C. L., Wang, X., Lehman, A., Lam, K., Toney, M. D., & Kurth, M. J. (2006). Aminodeoxychorismate synthase inhibitors from one-bead one-compound combinatorial libraries: "Staged" inhibitor design. Journal of Medicinal Chemistry, 49(25), 7413-7426. https://doi.org/10.1021/jm0609869