SBIR Phase I: Nonlinear optical method for identifying protein-ligand binding sites

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The broader impact of this Small Business Innovation Research (SBIR) Phase I project is to develop a technique that can reveal where precisely a small molecule, such as a potential drug, interacts with a protein on its surface. Proteins, particularly when mutated, are among the most frequent drivers of human disease. Drugs exert their effects by binding to the surface of a disease-causing protein and turning off the protein or otherwise changing its shape, which is critical for a protein’s function, so that the disease process is ameliorated or even halted. To develop effective drugs, a key piece of information is how and where on the surface precisely a small molecule binds to its target protein. This information is often challenging to obtain using conventional techniques such as X-ray crystallography or nuclear magnetic resonance (NMR). This project will develop a technique that could be used broadly for drug discovery. This Phase I project aims to develop a technique using a nonlinear optical method to identify the binding location of a small molecule on the surface of two cancer-causing proteins. Two proteins with small molecule ligands will be used to demonstrate feasibility of the technique, for which X-ray co-structures exist, providing a means to benchmark the findings of the proposed technique. The proposed technique will be based on a nonlinear optical technique that is sensitive to protein structure and ligand-induced conformational changes. The proteins will be labeled and detected by the optical technique, enabling measurements which will be analyzed to determine a ligand’s binding site.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.