Web Release Date: November 10,
Aminodeoxychorismate Synthase Inhibitors from One-Bead One-Compound Combinatorial Libraries: "Staged" Inhibitor Design
and
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, Department of Chemistry, Central Connecticut State University, 1615 Stanley Street, New Britain, Connecticut 06050, and Department of Internal Medicine, Division of Hematology and Oncology, UC Davis Cancer Center, 4501 X Street, Sacramento, California 95817
Received August 15, 2006
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 
M.
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.
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