Data belonging to the thesis: Corpora Non Agunt Nisi Fixata: Ligand Receptor Binding Kinetics in G Protein-Coupled Receptors.

The present thesis focuses on the pharmacological concept of drug-target interaction, which dates back to the beginning of modern pharmacology. A traditional equilibrium metrics-based rationale (i.e. optimization of drug affinity leads to better efficacy and safety) is unable to prevent current high attrition rates in the early phase of drug discovery. In the past decade drug-target binding kinetics (i.e. association and dissociation rate constants, residence time) has been gaining more and more attention, which constitutes a paradigm shift to better predict parameters of drug efficacy and safety. We decided to investigate binding kinetics of G protein-coupled receptors (GPCR), since GPCR are involved in various critical physiological and pharmacological functions, being the target of about 30% of all drugs on the market. Both the human cannabinoid receptor 1 and the human adenosine A1 and A3 receptors were chosen as prototypical GPCR as well as potential drug targets. The binding kinetics investigations described in this thesis provide a better and multi-faceted understanding of drug-target interactions and offer suggestions for the design of better ligands with an appropriate kinetic profile, new technologies for rapid kinetic assessment, and ultimately suitable evaluation schemes for a better translation towards effective and safe drugs.

本论文聚焦于药物-靶点相互作用这一可追溯至现代药理学发轫之初的药理学概念。传统的基于平衡态指标的研发逻辑（即优化药物亲和力可提升疗效与安全性）已无法遏制当前药物研发早期阶段居高不下的药物淘汰率。近十年来，药物-靶点结合动力学（即结合速率常数、解离速率常数与驻留时间）受到越来越多的关注，这一研究方向实现了范式转变，能够更精准地预测药物疗效与安全性相关参数。本研究选取G蛋白偶联受体（G protein-coupled receptors, GPCR）作为研究对象，探究其结合动力学特性，原因在于GPCR参与多种关键生理与药理学功能，且当前上市药物中约30%以其为作用靶点。本研究选取人类大麻素受体1与人类腺苷A1、A3受体作为典型GPCR与潜在药物靶点开展研究。本论文中开展的结合动力学研究，能够更为全面且多维度地阐明药物-靶点相互作用机制，并为以下方面提供指导：设计具备适宜动力学特性的优质配体、开发快速动力学评估的新技术，以及最终建立适配的评价体系，以更好地推动研发成果向高效安全药物的转化。