Turnkey THz Spectroscopy/Polarimetry System for Pharmaceutical Applications

摘要/总结 该项目第一阶段的成果将产生一个交钥匙系统的光谱/旋光在 太赫兹（0.8-3.0 THz）频率范围，旨在支持新药开发。该系统将直接 使用偏振太赫兹辐射探测蛋白质振动，使研究人员能够快速表征 分子内振动，这将有助于确定潜在药物靶点的蛋白质位点。通过查看 在不同相对分子取向之间的偏振光吸收的差异，振动 可以从通常使这些特征模糊的各向同性背景中分离出谐振。这 测量系统将使研究人员能够容易地安装蛋白质微晶，并立即获得 分子内振动指纹，以容易地看出该指纹是否以及如何随着单点而改变 突变或结合。分子内动力学的这种表征将在不需要引入 一个外部标签到研究中的系统。 在第一阶段项目期间将解决的主要技术障碍对 商业化是数据采集的极大简化。高亮度太赫兹源将是 开发的，这将允许基于强度的光谱数据的检测。该源将使用高功率 光纤激光器和准相位匹配的非线性晶体，以产生可调谐的窄带太赫兹输出。的 第二个技术改进将是偏振控制模块的开发，这将允许数据 无需移动样品即可进行采集，这是快速数据采集所必需的。最后，一个集成的示例 将开发保持器/检测模块，使用户能够轻松更换样本，而不会干扰 对准探测器。 在变构药物的设计中，关于长程结构振动的信息是特别感兴趣的， 与分子上远离活性位点的位置结合。目前对变构药物的兴趣是由于其 与正构药物（直接结合到活性位点的药物）相比具有明显的优势。目前，有研究 致力于更好地从根本上理解变构背后的机制， 目标是最终预测远端位点的作用如何调节蛋白质活性。这些信息将流 线药物发现的努力，降低成本的制药行业和药物的成本为患者。更 重要的是，它将通过加快药物发现过程和使药物在更大范围内发挥作用， 新药上市更快

ABSTRACT / SUMMARY The outcome of this phase 1 project will yield a turnkey system for spectroscopy/polarimetry in the terahertz (0.8-3.0 THz) frequency range, designed to support development of new drugs. This system will directly probe protein vibrations using polarized terahertz radiation, allowing researchers to rapidly characterize intramolecular vibrations, which will help identify sites on proteins for potential drug targets. By looking at differences in absorption of polarized light between different relative molecular orientations, vibrational resonances can be isolated from the isotropic background which generally obscure these features. This measurement system will enable a researcher to readily mount a protein microcrystal and immediately have the intramolecular vibrational fingerprint to readily see if and how this fingerprint has changed with single point mutations or binding. This characterization of intramolecular dynamics will be done without the need to introduce an external tag to the system under study. The main technological hurdle that will be addressed during this phase I project that will be crucial to the commercialization is the vast simplification of the data acquisition. A high brightness terahertz source will be developed that will allow intensity based detection of the spectroscopic data. This source will use a high power fiber laser and a quasi-phase matched nonlinear crystal to generate tunable, narrowband terahertz output. The second technological improvement will be the development of polarization control module, which will allow data acquisition without moving the sample, which is necessary for fast data collection. Finally, an integrated sample holder/detection module will be developed that allows users to easily change samples without disturbing the alignment into the detector. Information on long range structural vibrations is of particular interest in design of allosteric drugs, which bind to a location distant from the active site on a molecule. The current interest in allosteric drugs is due to their distinct advantages over orthosteric drugs (drugs that bind directly to the active site). Currently there are research efforts dedicated to gaining a better fundamental understanding of the mechanisms behind allostery, with the goal of eventually predicting how action at distant sites modulates protein activity. This information will stream line drug discovery efforts, reduce costs for the drug industry and cost of medications for the patients. More importantly, it will have a much broader societal impact by expediting the drug discovery process and making new drugs available faster.