Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions

J Am Chem Soc. 2009 Apr 22;131(15):5564-72. doi: 10.1021/ja810025g.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Design*
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Molecular Mimicry
  • Protein Binding / drug effects
  • Protein Structure, Secondary
  • Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Small Molecule Libraries / chemical synthesis*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Proteins
  • Small Molecule Libraries
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2