丰核使用化合物和蛋白组相互作用的方法研究药物及其靶点系统相互作用的文章发表在在国际专业一流期刊PLoS Comput Biol上.该研究通过比较氯氮平和奥氮平同蛋白质组之间的结合强度的差异确定了与粒细胞下降相关的关键蛋白,并且使用基因表达谱的芯片数据对结果进行了验证.这是杨仑博士在药物不良反应有关的系统药理学,个体化用药,以及老药新用方面的又一持续性的研究成果.

 

Exploring Off-Targets and Off-Systems for Adverse Drug Reactions via Chemical-Protein Interactome - Clozapine-Induced Agranulocytosis as a Case Study.

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.

http://www.ncbi.nlm.nih.gov/pubmed/21483481