SBIR Phase I: High-throughput drug discovery system

这个小企业创新研究（SBIR）第一阶段项目的更广泛的影响是帮助化学家找到能够持久坚持正确目标并在患者中更好地发挥作用的候选药物。通过过早地离开目标，药物停止工作，并可能从体内迅速清除。目前最先进的技术发现弱粘合剂并受到其他限制的困扰。本文提出的系统在药物发现和先导物优化期间以高通量测试大量化合物，从而取代具有低通量的当前系统。已确定的有效药物必须对预期靶点具有选择性。此外，该系统将为人工智能和分子动力学模拟提供信息，以优化预测药物性能的算法。该项目将通过提供高通量的动力学结果来优化药物设计，从而解决药物发现和先导优化中未满足的分析需求。所提出的新型仪器和分析化学系统测量化合物在目标上停留的时间。该解决方案将使用FDA批准的药物进行基准测试，这些药物使用变构作用机制来参与蛋白激酶AKT 1和AKT 2。 将使用新型试剂和商业仪器对抑制剂进行生化结合动力学、热力学分析和动力学测定中的激酶选择性分析。 将别构药物的解离率与文献报告进行比较。在几个温度下的分析将测量激酶释放变构药物的活化能。这些结果将成为成功批准药物的激酶-抑制剂相互作用的动力学和热力学基准。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.