The relationship between protein structure and function is fundamental for understanding the biological mechanisms that contribute to disease pathogenesis. Proteins are dynamic molecules that are capable of changing their shape, or conformation, in response to changes in their environment and upon ligand binding. Many important therapeutic protein targets undergo conformational change as part of their molecular mechanism of action. Recent drug development strategies have been focused on understanding the effects of small molecules on protein conformation, prompting efforts to rationally design specific and potent conformation-disrupting inhibitors. Thus, tools that can measure conformational changes induced by low- molecular weight modulators are necessary to accelerate the pace of basic research and the drug discovery process. We propose to acquire a Biodesy Delta system to complement the protein structure and characterization equipment that is currently available to investigators in the San Francisco Bay Area Region. The Biodesy Delta platform is based on an optical phenomenon called Second Harmonic Generation (SHG) which can be used to very precisely measure protein conformational changes in real-time following analyte binding or exposure to environmental stimuli. The system can work with any protein target, regardless of size, and a wide variety of ligands, including small molecules, fragments, proteins and mixtures. This high-throughput, automated method can be utilized to analyze thousands of wells per day, as opposed to standard methods that are low-throughput and labor intensive. The SHG conformational signatures provide a high-resolution means of mapping compound structures to function (e.g., activity data) via protein conformation. As a result, the Biodesy platform can be used to enhance primary screening and follow-up work, including protein structure-activity relationship (SAR) studies. Preliminary data that was generated by the major users demonstrates the utility of the SHG method for conducting initial library screening, as well as dose-response measurements, washout experiments, and real-time kinetics for hit triage. The proposed research will be conducted by 4 major PIs who oversee 16 NIH-funded grants. Additionally, 9 minor users will employ the technology in their current research projects. By obtaining the technology proposed in this grant, San Francisco Bay Area regional researchers will be uniquely positioned to accelerate protein characterization and drug discovery efforts. This tool will help revolutionize the understanding of the complex ligand-protein interactions that affect disease pathways which should ultimately lead to discovery of new therapeutics to improve human health.
Structural information is critical to understand the function or dysfunction of a protein and the mechanism of action of a drug targeted to that protein. Existing tools for measuring protein structure are expensive, slow, and labor intensive. Drug discovery and biological research have a pressing need for improved protein analysis tools with greater sensitivity, lower cost, and high throughput. The Biodesy Delta will allow researchers in the San Francisco Bay Area region (UCSF, Stanford, and UC Berkeley) to measure conformational change in proteins in a high-throughput, real-time fashion. Access to this tool will advance protein characterization and drug development efforts, and should ultimately lead to the discovery of new therapeutics to improve human health.
