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

这个小企业创新研究（SBIR）第一阶段项目的广泛影响是开发一种技术，可以精确地揭示小分子（如潜在药物）与表面蛋白质相互作用的位置。蛋白质，尤其是发生突变时，是人类疾病最常见的驱动因素之一。药物通过与致病蛋白质的表面结合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，因此疾病过程得到改善甚至停止。为了开发有效的药物，一个关键的信息是一个小分子如何以及在什么地方精确地与目标蛋白质结合。使用x射线晶体学或核磁共振（NMR）等传统技术通常很难获得这些信息。该项目将开发一种可广泛用于药物发现的技术。本一期项目旨在开发一种使用非线性光学方法识别两种致癌蛋白表面小分子结合位置的技术。两种带有小分子配体的蛋白质将被用来证明该技术的可行性，其中存在x射线共结构，为所提议的技术的发现提供了一种基准方法。该技术将基于对蛋白质结构和配体诱导构象变化敏感的非线性光学技术。这些蛋白质将通过光学技术进行标记和检测，从而进行测量分析，以确定配体的结合位点。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识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 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.