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

这个小企业创新研究（SBIR）第一阶段项目的更广泛的影响是开发一种技术，可以精确地揭示小分子（如潜在的药物）与其表面蛋白质相互作用的位置。蛋白质，特别是突变的蛋白质，是人类疾病最常见的驱动因素之一。 药物通过结合到致病蛋白质的表面并关闭蛋白质或以其他方式改变其形状来发挥作用，这对蛋白质的功能至关重要，从而改善甚至停止疾病过程。为了开发有效的药物，一个关键的信息是小分子如何以及在表面上的何处与其靶蛋白结合。使用常规技术（例如X射线晶体学或核磁共振（NMR））获得这些信息通常具有挑战性。 该项目将开发一种可广泛用于药物发现的技术。该项目的第一阶段旨在开发一种使用非线性光学方法的技术，以确定两种致癌蛋白质表面上小分子的结合位置。将使用两种具有小分子配体的蛋白质来证明该技术的可行性，其中存在X射线共结构，从而提供了一种对所提出的技术的发现进行基准测试的方法。所提出的技术将基于对蛋白质结构和配体诱导的构象变化敏感的非线性光学技术。蛋白质将被标记，并通过光学技术检测，使测量，将被分析，以确定配体的结合位点。这个奖项反映了NSF的法定使命，并已被认为是值得支持的评估使用基金会的智力价值和更广泛的影响审查标准。

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.