@article{pittir14153,
          volume = {7},
          number = {3},
           month = {March},
           title = {Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists},
          author = {D Koes and K Khoury and Y Huang and W Wang and M Bista and GM Popowicz and S Wolf and TA Holak and A D{\"o}mling and CJ Camacho},
            year = {2012},
         journal = {PLoS ONE},
             url = {http://d-scholarship-dev.library.pitt.edu/14153/},
        abstract = {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. {\copyright} 2012 Koes et al.}
}