题目：Where is the molecular action target?
主讲简介：Qing X. Li (李庆孝)，夏威夷大学马诺阿分校教授。研究专长：农用化学品和蛋白质组学。李庆孝教授，美国加州大学戴维斯分校博士，美国加州大学伯克利分校博士后，夏威夷大学马诺阿分校教授，夏威夷农药残留研究实验室主任。李庆孝教授主要研究方向为农用化学品和蛋白质组学，长期从事分子生物学研究，是酶联免疫反应在环境检测研究应用方面的权威专家，已发表SCI论文350余篇，他引5000余次。李庆孝教授是Journal of Agricultural and Food Chemistry副主编，Pesticide Biochemistry and Physiology等期刊编委。
主讲内容：Mechanism of action is pivotal of pharmacological studies and drug discovery. It involves identification and characterization of a specific molecular target to which the drug binds, such as an enzyme or receptor. This talk will discuss how the flavonoid isoorientin selectively inhibits glycogen synthase kinase-3β (GSK3β) in vitro. GSK3β emerges as an important therapeutic target in neurodegenerative diseases such as Alzheimer’s disease (AD). GSK3β is a key enzyme catalyzing hyperphosphorylation of tau protein. Selective inhibition of GSK3β is a promising therapeutic strategy for AD treatment. Semi-synthesis of isoorientin has led greater than 300 fold potency improvement. Enzyme kinetic studies and molecular modeling demonstrated that both isoorientin and its synthetic analogs specifically inhibit GSK3β via a substrate competitive, rather than the common ATP competitive mode. Structure-activity relationship analyses and in silico modeling suggest the mechanism of actions by which the hydrophobic, π-cation and orthogonal multipolar interactions are involved for the GSK3β inhibition and selectivity. Cellular studies further demonstrated that those flavonoids effectively attenuate GSK3β-catalyzed tau hyperphosphorylation and is neuroprotective against amyloid-induced neurotoxicity in human SH-SY5Y cells. The new inhibitors are valuable chemical probes and drug leads with therapeutic potential to tackle AD and other GSK-3β relevant diseases.