药物与蛋白质相互作用发光模型及其药代动力学研究

It is significant on theoretical, academic and applicable aspects studying of the interaction of protein with drug to expound the pharmacological activity and pharmacokinetics of drug. .In this project, the photochemical mechanism of protein with drug is investigated by luminescence with flow injection (FI) analysis. Using the FI-chemiluminescence (CL) signal from online generated luminol-functional protein as steady state light source, the FI-CL model of the interaction for protein with small molecule is established based on the light absorbance or emission (enhancement or quenching) of protein-small molecule complex, and that the relative CL intensity is linear with the concentration of small molecule, giving the binding constant, the number of binding site, binding type, sensitivity factor and thermodynamic parameters, etc. By X-ray method, according to the 3D data of crystalline protein-drug complex, the accurate binding site of protein with drug can be obtained, and the evaluation between molecular structure, properties and pharmacological activity of drug and the conformation and function of protein is explored to provide new method and technique for the basic research of protein with drug. .Human saliva, in which many clinically relevant analytes and drug concentrations can generally reflect the levels in tissue fluid or plasma, is increasingly becoming a welcome and accepted biological matrix in diagnostic research and clinical chemistry. Through the simple and convenient saliva sampling, the continuous monitoring drug at picomolar-level by FI-CL analysis is proposed for the first time. Based on the drug concentration in human saliva and studying the pharmacokinetics, a complete personalized diagnosis in the early stage can be given for a specific disease and a group of patients, and a simple, fast, sensitive and practical detection evaluation method for clinical use can be provided.

研究蛋白质与药物相互作用对阐明药物的药理活性和药代动力学具有重要的理论意义、学术价值和应用前景。本课题拟以发光剂-功能蛋白质在线产生的化学发光信号为稳态光源，以功能蛋白质与小分子相互作用生成的复合体(或配合物)对该稳态光源的吸收或发射(增敏或猝灭)为基础，建立蛋白质与小分子相互作用的流动注射化学发光分析模型(FI-CL model)，给出蛋白质与小分子相互作用的结合常数、结合位点数、作用类型、灵敏度因子及热力学参数等；探索药物分子结构、性质和药理活性与蛋白质构象和功能之间的相关性，为药物对蛋白质作用的基础研究提供新思路、新方法和新技术；采用经济简便的唾液取样，通过监测人体唾液中药物浓度, 进行药物代谢动力学研究，拟为特定疾病和一类病人提供完整的早期个体诊断，为临床寻找一种简单、快速、灵敏、实用的检测评价方法；该微流动检测系统将为仪器的自动化、微型化、便携式奠定基础。

研究与探讨结构相似的小分子与蛋白质相互作用的规律性，不仅有助于指导药物设计及筛选等过程，而且可为药物代谢动力学提供重要信息。本课题以发光剂-功能蛋白质在线产生的化学发光信号为稳态光源，以功能蛋白质与小分子相互作用生成的复合体（或配合物）对稳态光源的吸收或发射（增敏或猝灭）为基础，成功建立了蛋白质与小分子相互作用的流动注射化学发光模型（FI-CL model），给出了蛋白质与小分子相互作用的结合常数、结合位点数、作用类型、灵敏度因子及热力学参数等；探索了多种药物分子结构、性质和药理活性与蛋白质构象和功能的相关性，为两者之间相互作用研究提供了新思维。以无损采样方式，通过检测人体唾液和尿液中的药物浓度，开展了药物代谢动力学分析工作，成功获得了吸收速率常数、消除速率常数、消除半衰期等参数，对临床疾病诊断、治疗药物检测等有重要的实际意义。