上海交通大學(xué)Bio-X研究院生物信息研究中心近期由博士生王可鑒和技術(shù)員陳劍作為主要參與人在《PLoS計算生物學(xué)》雜志上發(fā)表論文,，用基于"化合物-蛋白互作組"（chemical-protein interactome, CPI）的方法論體系研究靶蛋白和靶系統(tǒng)偏差引發(fā)藥物不良反應(yīng)和老藥新用的系統(tǒng)生物學(xué)機制,。該研究利用"差異CPI",，通過對比抗精神藥物氯氮平（可引起粒細(xì)胞下降的不良反應(yīng)）和與之在結(jié)構(gòu)、藥理等方面十分相似的奧氮平（不良反應(yīng)報告較少）與數(shù)百個人類蛋白之間結(jié)合強度的差異,，成功定位出與粒細(xì)胞下降相關(guān)的關(guān)鍵蛋白,；同時,，基于對氯氮平處理細(xì)胞的基因表達譜芯片的數(shù)據(jù)挖掘,，驗證了受與這些基因相關(guān)的偏差靶系統(tǒng),。從而為藥物不良反應(yīng)的系統(tǒng)藥理學(xué)、個體化用藥和基于系統(tǒng)的老藥新用等方面的研究提供了創(chuàng)造性和堅實的理論依據(jù),。
此研究由賀林院士和美國FDA訪問學(xué)者楊侖博士領(lǐng)導(dǎo),，由國家自然科學(xué)基金青年基金，國家863,、973計劃資助,，并得到美國FDA相關(guān)部門和專家的積極支持和肯定。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
論文url: http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002016
