Rational design of topographical helix mimics as potent inhibitors of protein-protein interactions

J Am Chem Soc. 2014 Jun 4;136(22):7877-88. doi: 10.1021/ja502310r. Epub 2014 May 23.

Abstract

Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors. Experimental screening of focused compound libraries is used to further optimize inhibitors but the number of possible designs that can be efficiently synthesized and experimentally tested in academic settings is limited. We have applied the principles of computational protein design to optimization of nonpeptidic helix mimics as ligands for protein complexes. We describe the development of computational tools to design helix mimetics from canonical and noncanonical residue libraries and their application to two therapeutically important protein-protein interactions: p53-MDM2 and p300-HIF1α. The overall study provides a streamlined approach for discovering potent peptidomimetic inhibitors of protein-protein interactions.

Publication types

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

MeSH terms

  • Amino Acids / chemistry
  • Computational Biology
  • Drug Design
  • E1A-Associated p300 Protein / antagonists & inhibitors
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Models, Molecular
  • Molecular Mimicry
  • Protein Binding / drug effects
  • Protein Structure, Secondary
  • Proteins / chemistry*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Small Molecule Libraries
  • Tumor Suppressor Protein p53 / antagonists & inhibitors

Substances

  • Amino Acids
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Proteins
  • Small Molecule Libraries
  • Tumor Suppressor Protein p53
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2