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Enabling Large-Scale Design, Synthesis and Validation of Small Molecule Protein-Protein Antagonists

Published: Friday, April 13, 2012
Last Updated: Friday, April 13, 2012
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With the number of new drug applications (NDA) on the decline, a new approach that stops our dependence from old compounds, and utilizes the vast information available on protein interactions and structure, is desperately needed.

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.

This paper is published online in PLos ONE and is free to access.

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