High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics

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	High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics
	Pan, Jian-Bo ; Ji, Nan ; Pan, Wen ; Hong, Ru ; Wang, Hao ; Ji, Zhi-Liang ; Ji ZL(纪志梁)
刊名	http://dx.doi.org/10.1016/j.taap.2013.10.017
	2014
关键词	LEFT-VENTRICULAR HYPERTROPHY CARDIOVASCULAR-DISEASE HEART-DISEASE CYCLOOXYGENASE-2 INHIBITOR INDUCED TOXICITY OPIOID-RECEPTOR PROTEIN TARGETS LUNG-FUNCTION RISK-FACTORS MICE
英文摘要	Natural Science Foundation of China (NSFC) [31271405]; Fundamental Research Funds for the Central Universities of MOE [2010121084]; Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPs that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.
语种	英语
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/90857]
专题	生命科学－已发表论文
推荐引用方式 GB/T 7714	Pan, Jian-Bo,Ji, Nan,Pan, Wen,et al. High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics[J]. http://dx.doi.org/10.1016/j.taap.2013.10.017,2014.
APA	Pan, Jian-Bo.,Ji, Nan.,Pan, Wen.,Hong, Ru.,Wang, Hao.,...&纪志梁.(2014).High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics.http://dx.doi.org/10.1016/j.taap.2013.10.017.
MLA	Pan, Jian-Bo,et al."High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics".http://dx.doi.org/10.1016/j.taap.2013.10.017 (2014).