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Identification of drug-induced myocardial infarction-related protein targets through the prediction of drug-target interactions and analysis of biological processes.

Abstract：

:Drug-induced myocardial infarction (DIMI) is one of the most serious adverse drug effects that often lead to death. Therefore, the identification of DIMI at the early stages of drug development is essential. For this purpose, the in vitro testing and in silico prediction of interactions between drug-like substances and various off-target proteins associated with serious adverse drug reactions are performed. However, only a few DIMI-related protein targets are currently known. We developed a novel in silico approach for the identification of DIMI-related protein targets. This approach is based on the computational prediction of drug-target interaction profiles based on information from approximately 1738 human targets and 828 drugs, including 254 drugs that cause myocardial infarction. Through a statistical analysis, we revealed the 155 most significant associations between protein targets and DIMI. Because not all of the identified associations may lead to DIMI, an analysis of the biological functions of these proteins was performed. The Random Walk with Restart algorithm based on a functional linkage gene network was used to prioritize the revealed DIMI-related protein targets according to the functional similarity between their genes and known genes associated with myocardial infarction. The biological processes associated with the 155 selected protein targets were determined by gene ontology and pathway enrichment analysis. This analysis indicated that most of the processes leading to DIMI are associated with atherosclerosis. The revealed proteins were manually annotated with biological processes using functional and disease-related data extracted from the literature. Finally, the 155 protein targets were classified into three categories of confidence: (1) high (the protein targets are known to be involved in DIMI via atherosclerotic progression; 50 targets), (2) medium (the proteins are known to participate in biological processes related with DIMI; 65 targets), and (3) low (the proteins are indirectly involved in DIMI pathogenesis; 40 proteins).

journal_name

Chem Res Toxicol

journal_title

Chemical research in toxicology

authors

Ivanov SM,Lagunin AA,Pogodin PV,Filimonov DA,Poroikov VV

doi

10.1021/tx500147d

subject

Has Abstract

pub_date

2014-07-21 00:00:00

pages

1263-81

issue

eissn

0893-228X

issn

1520-5010

journal_volume

pub_type

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Identification of drug-induced myocardial infarction-related protein targets through the prediction of drug-target interactions and analysis of biological processes.