Developing NMR and Biophysical Strategies to Study Protein-Ligand Interactions and Reveal Interesting Compound Properties

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There is a widely held view that the study of ligands binding to macromolecules should be simple and straightforward. In practice, however, the available tools are sparse and compromised by artifacts. Moreover, binding involves many events, some of which have yet to be fully revealed. This research program aims to develop strategies to enable the elucidation of various binding events and to expose relevant free-state properties of small-molecule ligands. The research will be executed within the context of mounting fragment-based ligand discovery (FBLD) efforts in my laboratory where the binding of thousands of compounds to a variety of protein types will be systematically evaluated. Briefly, FBLD will involve the screening of libraries (e.g. ~1000-8000 members) of fragment compounds (~120-300 Da) in search for binders (K