title: Rapid discovery of potent sulfotransferase inhibitors by diversity-oriented reaction in microplates followed by in situ screening.
abstract: Rapid diversity-oriented microplate library synthesis and in situ screening with a high-throughput fluorescence-based assay were used to develop potent inhibitors of beta-arylsulfotransferase IV (beta-AST-IV). This strategy leads to facile inhibitor synthesis and study as it allows protecting-group manipulation and product isolation from other library components to be avoided. Through repeated library formation, three aspects of inhibitor makeup, the identities of the two binding groups and the length of the linker between them, were independently optimized. Several potent inhibitors were obtained, one of which was determined to have an inhibition constant K(i) of 5 nM. This compound is the most potent beta-AST-IV inhibitor developed to date, with a K(i) value more than five orders of magnitude lower than the Michaelis constant K(m) for the substrate whose binding it inhibits.
authors.affiliation: Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Best
authors.forename: Ashraf
authors.initials: A
authors.lastname: Brik
authors.forename: Eli
authors.initials: E
authors.lastname: Chapman
authors.forename: Lac V
authors.initials: LV
authors.lastname: Lee
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Cheng
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005453:Fluorescence; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D015238:Sulfotransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D015238:Sulfotransferases; C077557:tyrosine-ester sulfotransferase