title: A one-bead, one-stock solution approach to chemical genetics: part 1.
abstract: BACKGROUND
  In chemical genetics, small molecules instead of genetic mutations are used to modulate the functions of proteins rapidly and conditionally, thereby allowing many biological processes to be explored. This approach requires the identification of compounds that regulate pathways and bind to proteins with high specificity. Structurally complex and diverse small molecules can be prepared using diversity-oriented synthesis, and the split-pool strategy allows their spatial segregation on individual polymer beads, but typically in quantities that limit their usefulness.
  
  
  RESULTS
  We report full details of the first phase of our platform development, including the synthesis of a high-capacity solid-phase bead/linker system, the development of a reliable library encoding strategy, and the design of compound decoding methods both from macrobeads and stock solutions. This phase was validated by the analysis of an enantioselective, diversity-oriented synthesis resulting in an encoded 4320-member library of structurally complex dihydropyrancarboxamides.
  
  
  CONCLUSIONS
  An efficient and accessible approach to split-pool, diversity-oriented synthesis using high-capacity macrobeads as individual microreactors has been developed. Each macrobead contains sufficient compound to generate a stock solution amenable to many biological assays, and reliable library encoding allows for rapid compound structure elucidation post-synthesis. This 'one-bead, one-stock solution' strategy is a central element of a technology platform aimed at advancing chemical genetics.
authors.affiliation: Howard Hughes Medical Institutes at Harvard University, Cambridge, MA 02138, USA.
authors.forename: H E
authors.initials: HE
authors.lastname: Blackwell
authors.forename: L
authors.initials: L
authors.lastname: Pérez
authors.forename: R A
authors.initials: RA
authors.lastname: Stavenger
authors.forename: J A
authors.initials: JA
authors.lastname: Tallarico
authors.forename: E
authors.initials: E
authors.lastname: Cope Eatough
authors.forename: M A
authors.initials: MA
authors.lastname: Foley
authors.forename: S L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D020650:Combinatorial Chemistry Techniques / Q000379:methods; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis* / Q000737:chemistry*; D008863:Microspheres; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis* / Q000235:genetics*
chemical_list: D006841:Hydrocarbons, Aromatic; D019151:Peptide Library; D010455:Peptides