1: J Med Chem. 2006 Dec 14;49(25):7413-26. 

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

Dixon S, Ziebart KT, He Z, Jeddeloh M, Yoo CL, Wang X, Lehman A, Lam KS, Toney
MD, Kurth MJ.

Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, USA.

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 Mg(2+). The most potent ADCS inhibitor identified has a
K(i) of 360 microM. 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.

Publication Types:
    Research Support, U.S. Gov't, Non-P.H.S.

PMID: 17149871 [PubMed - in process]