SBIR Phase I: High-throughput drug discovery system

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The broader impact of this Small Business Innovation Research (SBIR) Phase I project is to help chemists find drug candidates that can stick persistently to the correct target and work better in patients. By coming off the target prematurely, a drug stops working and may be cleared rapidly from the body. Current state-of-the-art technologies find weak binders and are plagued by other limitations. The system proposed herein tests large numbers of compounds at high throughput during drug discovery and lead optimization, replacing current systems with low throughput. The identified effective drugs must be selective to the intended target. Furthermore, the proposed system will inform Artificial Intelligence and Molecular Dynamics simulations for optimized algorithms predicting drug performance.The proposed project will solve an unmet analytical need in drug discovery and lead optimization by providing kinetic results at high throughput to refine drug designs. The proposed novel instrument and assay chemistry system measures how long chemical compounds stay on target. The solution will be benchmarked using FDA-approved drugs that use an allosteric mechanism of action to engage protein kinases AKT1 and AKT2. Inhibitors will be profiled for biochemical binding kinetics, thermodynamic analysis, and kinase selectivity in kinetic assays using novel reagents and commercial instrumentation. Dissociation rates for the allosteric drugs will be compared with literature reports. Analysis at several temperatures will measure the activation energy for the kinase to release the allosteric drug. The results will be a benchmark profile of kinetics and thermodynamics for kinase-inhibitor interactions of successful approved drugs. An advanced instrument will be built and tested in endpoint mode for sample handling, signal linearity, background and dynamic range using control reagents.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.