title: Aminodeoxychorismate synthase inhibitors from one-bead one-compound combinatorial libraries: "staged" inhibitor design.
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 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.
authors.affiliation: Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Dixon
authors.forename: Kristin T
authors.initials: KT
authors.lastname: Ziebart
authors.forename: Ze
authors.initials: Z
authors.lastname: He
authors.forename: Melissa
authors.initials: M
authors.lastname: Jeddeloh
authors.forename: Choong Leol
authors.initials: CL
authors.lastname: Yoo
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Wang
authors.forename: Alan
authors.initials: A
authors.lastname: Lehman
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
authors.forename: Michael D
authors.initials: MD
authors.lastname: Toney
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kurth
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002413:Cations, Divalent; D002827:Chorismic Acid / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D005456:Fluorescent Dyes; D062425:Hydroxybenzoate Ethers; D007700:Kinetics; D008274:Magnesium / Q000737:chemistry; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D010642:Phenoxyacetates / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D012117:Resins, Synthetic; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000637:Transaminases
chemical_list: C517235:3-(carboxymethoxy)benzoic acid; D000085:Acetates; D000890:Anti-Infective Agents; D001565:Benzoates; D002413:Cations, Divalent; D005456:Fluorescent Dyes; D062425:Hydroxybenzoate Ethers; D019151:Peptide Library; D010455:Peptides; D010642:Phenoxyacetates; D012117:Resins, Synthetic; D000637:Transaminases; C066599:aminodeoxychorismate synthase; D019731:Carbon-Nitrogen Ligases; D002827:Chorismic Acid; D008274:Magnesium