上海交通大学Bio-X研究院生物信息研究中心近期由博士生王可鉴和技术员陈剑作为主要参与人在《PLoS计算生物学》杂志上发表论文，用基于"化合物-蛋白互作组"（chemical-protein interactome, CPI）的方法论体系研究靶蛋白和靶系统偏差引发药物不良反应和老药新用的系统生物学机制。该研究利用"差异CPI"，通过对比抗精神药物氯氮平（可引起粒细胞下降的不良反应）和与之在结构、药理等方面十分相似的奥氮平（不良反应报告较少）与数百个人类蛋白之间结合强度的差异，成功定位出与粒细胞下降相关的关键蛋白；同时，基于对氯氮平处理细胞的基因表达谱芯片的数据挖掘，验证了受与这些基因相关的偏差靶系统。从而为药物不良反应的系统药理学、个体化用药和基于系统的老药新用等方面的研究提供了创造性和坚实的理论依据。
此研究由贺林院士和美国FDA访问学者杨仑博士领导，由国家自然科学基金青年基金，国家863、973计划资助，并得到美国FDA相关部门和专家的积极支持和肯定。（生物谷Bioon.com）
生物谷推荐原文出处：
PLoS Comput Biol 7(3): e1002016. doi:10.1371/journal.pcbi.1002016
Exploring Off-Targets and Off-Systems for Adverse Drug Reactions via Chemical-Protein Interactome — Clozapine-Induced Agranulocytosis as a Case Study
Lun Yang1,2,3#¤*, Kejian Wang1#, Jian Chen1, Anil G. Jegga4,5, Heng Luo1, Leming Shi3, Chunling Wan1, Xizhi Guo1, Shengying Qin1, Guang He1, Guoyin Feng1, Lin He1,2,6*
1 Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China, 2 Institutes of Biomedical Sciences, Fudan University, Shanghai, China, 3 School of Pharmacy, Fudan University, Shanghai, China, 4 Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America, 5 Departments of Pediatrics and Computer Science, University of Cincinnati, Cincinnati, Ohio, United States of America, 6 Institute for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Abstract
In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.
论文url: http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002016
