基于五羟色胺2C受体与药物小分子氯卡色林复合物结构的结合特异性改善及功能验证研究

G protein-coupled receptors (GPCRs) are cell surface receptors which are involved in a wide range of physiological activities and constitute the largest human protein family with over 800 members. Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter widely found in both the central nervous system (CNS) and the peripheral nervous system. In the CNS, serotonergic system regulates mood, perception, memory, food intake, sexual behaviors, and others. Due to the high similarities of ligand binding pockets among serotonin receptors, most of the marketed drugs targeting serotonin receptors have unwanted side effects resulted from their low specificity. For example, lorcaserin, which targets at 5-HT2C, is an anti-obesity drug on the market. However, due to its low specificity, lorcaserin activates 5-HT2A and leads to hallucinogenic effects, and its interaction with 5-HT2B causes valvular heart disease. The objective of this project is to study the interaction between lorcaserin and 5-HT2C using structural biology method. We’ll perform structure based chemical scaffold modification of lorcaserin for increasing its binding specificity to 5-HT2C, followed by functional validation. We hope our study will provide theoretical and experimental foundation for the next generation anti-obesity drug targeting 5-HT2C without unwanted side effects.

G蛋白偶联受体作为细胞表面膜蛋白受体调控人体内众多的生理和病理活动。五羟色胺作为一种神经递质广泛存在于神经系统中, 调节人的情绪，记忆，认知，食欲，性功能等，因此五羟色胺受体家族成为肥胖、抑郁及神经分裂等病症的重要药物靶标。但由于该受体家族成员间结合配体区域的氨基酸组成非常保守，导致针对五羟色胺受体亚型的药物特异性不高，易产生副作用。例如靶向五羟色胺2C受体的氯卡色林（lorcaserin）是目前市场在售的减肥药，但其脱靶作用到五羟色胺2A受体的副作用是产生幻觉，作用到五羟色胺2B受体的副作用是心脏瓣膜的疾病。本项目拟使用结构生物学方法研究氯卡色林与五羟色胺2C受体的相互作用及下游信号调控机制，并在此基础上通过基于结构的化学小分子改造和功能验证，探索改善氯卡色林对五羟色胺2C受体的结合特异性，以避免其与五羟色胺2A及2B结合导致的副作用。为开发靶向五羟色胺2C受体的新型药物提供坚实理论。

G蛋白偶联受体作为细胞表面膜蛋白受体调控人体内众多的生理和病理活动。五羟色胺作为一种神经递质广泛存在于神经系统中, 调节人的情绪，记忆，认知，食欲，性功能等，因此五羟色胺受体（GPCR受体之一）家族成为肥胖、抑郁及神经分裂等病症的重要药物靶标。本项目深度与药物化学团队合作，使用结构生物学方法研究五羟色胺2C受体与以药物小分子氯卡色林(lorcaserin)为灵感而设计的偏好性激活剂的相互作用及下游信号调控机制，并在此基础上通过基于结构的化学小分子改造和功能验证，探索偏好性激活剂对五羟色胺2C受体的结合特异性以及偏向性激活下游信号蛋白的分子机制，为开发靶向五羟色胺2C受体的新型药物提供坚实理论。