Probing Protein Surfaces: QSAR Analysis with Helix Mimetics

Chembiochem. 2016 Apr 15;17(8):768-73. doi: 10.1002/cbic.201500504. Epub 2016 Jan 21.

Abstract

α-Helix-mediated protein-protein interactions (PPIs) are important targets for small-molecule inhibition; however, generic approaches to inhibitor design are in their infancy and would benefit from QSAR analyses to rationalise the noncovalent basis of molecular recognition by designed ligands. Using a helix mimetic based on an oligoamide scaffold, we have exploited the power of a modular synthesis to access compounds that can readily be used to understand the noncovalent determinants of hDM2 recognition by this series of cell-active p53/hDM2 inhibitors.

Keywords: chemical biology; foldamers; helix mimetics; p53/hDM2; protein-protein interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Protein Binding / drug effects
  • Protein Structure, Secondary
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / chemistry*
  • Quantitative Structure-Activity Relationship*
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Surface Properties
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / chemistry*

Substances

  • Ligands
  • Small Molecule Libraries
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2