【作者】 古江勇； 罗芳； 陈丽蓉； 徐筱杰；

【Author】 Jiangyong Gu;Fang Luo;Lirong Chen;Xiaojie Xu;College of Chemistry and Molecular Engineering, Peking University;

【机构】 北京大学化学与分子工程学院；

【摘要】 生物通路(pathway)可视为执行特定生物功能的最小的生物系统。在基于生物通路的网络模型中,网络中的节点代表蛋白、核酸和小分子等,它们之间的边代表在细胞内或细胞间的相互作用或信号转导过程。网络中边与节点的打断或抑制将会影响到网络的完整性,使网络中节点的相互作用效果减弱。网络效率和网络流量反映网络的完整性,是度量网络连通性的拓扑学属性。药物抑制生物通路中的靶蛋白将导致网络效率和网络流量的降低,据此可评价化合物的药效。通过构建LPS诱导的PGE2释放的生物通路网络并采用Michaelis-Menten方程和网络效率及网络流量来预测药物在不同浓度时的药效,以LPS诱导的RAW264.7细胞实验进行验证。综合考虑网络效率和网络流量,预测的药效与实验结果吻合较好,相关系数为0.96。本方法也可用于两个或多个药物的组合,用量-效曲面及等效线图表征。计算结果表明当两个药物以各自的IC50比例进行组合时可得到最佳协同效果,在降低剂量的同时提高药效。更多还原

【Abstract】 Biological pathway can be regarded as the minimal biosystem which can exert a specific function. Network efficiency(NE) and network flux(NF) are both measures of the network connectivity. NE and NF were used to quantitatively evaluate the inhibitory effects of compounds against the production of prostaglandin E2(PGE2) in LPS-induced RAW264.7 cells. First, the pathway of LPS-induced PGE2 release was built according to literatures and databases. Then the edge values were reset according to the Michaelis-Menten equation, which used the binding constant(Ki) and drug concentration to determine the degree of inhibition of the target protein in the pathway. Finally, the combination of NE and NF(NEF) was adopted to evaluate the inhibitory effect. The predicted IC50 of five compounds were in good agreement with experimental results(R=0.96). Moreover, we calculated the inhibitory effects of drug combinations at different concentrations and found that two drugs would produce maximum synergism if they were combined according to the proportion of each IC50.更多还原