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 Citations (Scopus)

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

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Catalytic Domain
Screening
para-Aminobenzoates
Folic Acid
Libraries
Fluorescence
Kinetics
aminodeoxychorismate synthase

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Aminodeoxychorismate synthase inhibitors from one-bead one-compound combinatorial libraries : "Staged" inhibitor design. / Dixon, Seth; Ziebart, Kristin T.; He, Ze; Jeddeloh, Melissa; Yoo, Choong Leol; Wang, Xiaobing; Lehman, Alan; Lam, Kit; Toney, Michael D.; Kurth, Mark J.

In: Journal of Medicinal Chemistry, Vol. 49, No. 25, 14.12.2006, p. 7413-7426.

Research output: Contribution to journalArticle

Dixon, S, Ziebart, KT, He, Z, Jeddeloh, M, Yoo, CL, Wang, X, Lehman, A, Lam, K, Toney, MD & Kurth, MJ 2006, 'Aminodeoxychorismate synthase inhibitors from one-bead one-compound combinatorial libraries: "Staged" inhibitor design', Journal of Medicinal Chemistry, vol. 49, no. 25, pp. 7413-7426. https://doi.org/10.1021/jm0609869
Dixon, Seth ; Ziebart, Kristin T. ; He, Ze ; Jeddeloh, Melissa ; Yoo, Choong Leol ; Wang, Xiaobing ; Lehman, Alan ; Lam, Kit ; Toney, Michael D. ; Kurth, Mark J. / Aminodeoxychorismate synthase inhibitors from one-bead one-compound combinatorial libraries : "Staged" inhibitor design. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 25. pp. 7413-7426.
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