1878-61-1Relevant articles and documents
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 S.,Toney, Michael D.,Kurth, Mark J.
, p. 7413 - 7426 (2007/10/03)
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.
