title: Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions.
abstract: The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Shaginian
authors.forename: Landon R
authors.initials: LR
authors.lastname: Whitby
authors.forename: Sukwon
authors.initials: S
authors.lastname: Hong
authors.forename: Inkyu
authors.initials: I
authors.lastname: Hwang
authors.forename: Bilal
authors.initials: B
authors.lastname: Farooqi
authors.forename: Mark
authors.initials: M
authors.lastname: Searcey
authors.forename: Jiandong
authors.initials: J
authors.lastname: Chen
authors.forename: Peter K
authors.initials: PK
authors.lastname: Vogt
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger