Enabling Large-Scale Design, Synthesis and Validation of Small Molecule Protein-Protein AntagonistsReportar como inadecuado




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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.



Autor: David Koes, Kareem Khoury, Yijun Huang, Wei Wang, Michal Bista, Grzegorz M. Popowicz, Siglinde Wolf, Tad A. Holak, Alexander Döm

Fuente: http://plos.srce.hr/



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