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 journalArticlepeer-review

20 Scopus citations


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
Issue number25
StatePublished - Dec 14 2006

ASJC Scopus subject areas

  • Organic Chemistry


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