R21: ANCHOR: A PDB-Wide And Web-based Discovery Resource of Small Molecular Weight Protein Interaction (Ant)agonists. PI: Alexander Doemling Departments of Pharmacy and Chemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA PI: Carlos J. Camacho Department of Computational Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA Abstract Protein-protein interactions (PPIs) constitute an emerging class of targets for pharmaceutical intervention with the PDB providing a highly valuable source for structural information. However, the diversity of PPIs does not fit well in the current drug discovery paradigm that focus almost exclusively on screening large historical collections of (commercially available) small molecular weight compounds. Despite computational limitations on the sampling of chemical space and scoring of protein-small molecule docked conformations, in silico screening methods continue to be developed and improved as credible and complementary alternatives to high-throughput biochemical compound screening (HTS). The ultimate goal of this proposal is to overcome these limitations by developing a virtual screening technology of virtual libraries that by design have a built-in amino acid hot spot, or """"""""anchor,"""""""" that is burying deep into acceptor proteins complemented with real multi-component reaction (MCR) chemistry.
Specific aims are to (a) classify the PDB based on their drug-like susceptibility such as single anchors or higher motifs, doublets and triplets of amino-acids;(b) develop a unique set of anchor- analogs for the 20 amino acids and a database of >100 small molecular weight scaffolds to create a novel virtual, but chemically accessible, library to target pre-screened protein-protein interactions;(c) set up a systematic virtual screening of the PPIs based on the pre-docking of anchor-analogs to the PPI complex structure;and (d), provide a public resource for the prediction of (ant)agonists based on novel compounds, while proactively contact structural groups with easy access to the target protein to establish collaborations where compounds will be rapidly synthesized in a one-pot manner (i.e., using MCR) for validation. A PDB wide mapping of drug-like targets combined with novel compounds specifically designed to mimic the chemistry and structure of deeply buried anchor residues of PPIs is an original approach to discover (ant)agonists as tools to elucidate biological pathways or as starting points for medicinal chemistry programs.
-Relevance While the number of well characterized protein-protein interactions (PPI) increases by the thousands, the number of these PPIs that are targets of drug discovery initiatives is very small. By developing a truly virtual screening technology of virtual libraries that by design have a built-in amino acid hot spot, or anchor, that is burying deep into acceptor proteins complemented with experimental multi-component reaction (MCR) chemistry, this proposal will create a publicly accessible resource that facilitates the discovery of (ant)agonists as tools to elucidate biological pathways or as starting points for medicinal chemistry programs.
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