%0 Journal Article
%T Enabling Large-Scale Design, Synthesis and Validation of Small Molecule Protein-Protein Antagonists
%A David Koes
%A Kareem Khoury
%A Yijun Huang
%A Wei Wang
%A Michal Bista
%A Grzegorz M. Popowicz
%A Siglinde Wolf
%A Tad A. Holak
%A Alexander D£żmling
%A Carlos J. Camacho
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0032839
%X 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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0032839