title: High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics.
abstract: 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.
authors.affiliation: Department of Chemical Biology, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005, PR China.
authors.forename: Jian-Bo
authors.initials: JB
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, PR China.
authors.forename: Ru
authors.initials: R
authors.lastname: Hong
authors.affiliation: Department of Chemical Biology, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, PR China; Department of Chemical Biology, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005, PR China. Electronic address: appo@xmu.edu.cn.
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Ji
mesh_terms: D000700:Analgesics / Q000009:adverse effects* / Q000633:toxicity; D000818:Animals; D003198:Computer Simulation; D016503:Drug Delivery Systems / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis* / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D011485:Protein Binding / Q000502:physiology
chemical_list: D000700:Analgesics
keywords: ADR-associated proteins; ADR-associated proteins (ADRAPs); ADRAPs; CAs; CDs; LDs; Off-target mechanism; SADRs; Severe adverse drug reactions (SADRs); cardiac arrhythmias; cardiac disorders; lung disorders; severe adverse drug reactions