The site-identification by ligand competitive saturation (SILCS) approach is extended to the identification of fragment bindings sites, termed SILCS Hotspots. The approach involves an initial precomputation of the SILCS FragMaps following which the identification of potential binding sites of fragments is performed by posing and ranking each fragment against the entire 3D structure of the target macromolecule followed by spatial clustering from which multiple local binding sites are identified. This approach allows for the identification of a large number of sites on the target protein, including many sites not accessible in experimental structures. Notable is the ability of the approach to identify sites on the protein interior. In addition, exclusion maps from SILCS simulations allow for identification of putative accessible paths through the protein that are required to covalently link fragments occupying adjacent Hotspots to create drug-like molecules. The potential utility of the SILCS-Hotspots approach for fragment-based rational design of ligands, including allosteric modulators will be presented.

Identification and characterization of fragment binding sites for allosteric ligand design using site identification by ligand competitive saturation (SILCS)

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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