Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists

David Koes, Kareem Khoury, Yijun Huang, Wei Wang, Michal Bista, Grzegorz M Popowicz, Siglinde Wolf, Tad A Holak, Alexander Dömling, Carlos J Camacho

Research output: Contribution to journalArticleAcademicpeer-review

86 Citations (Scopus)
185 Downloads (Pure)


Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure.

Original languageEnglish
Article numbere32839
Number of pages8
JournalPLoS ONE
Issue number3
Publication statusPublished - 12-Mar-2012
Externally publishedYes


  • Chemistry, Pharmaceutical
  • Crystallography
  • Drug Discovery
  • Internet
  • Protein Interaction Mapping
  • Proto-Oncogene Proteins c-mdm2
  • Small Molecule Libraries
  • Software
  • Systems Biology
  • Tumor Suppressor Protein p53


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