TY - JOUR
T1 - Relating drug-protein interaction network with drug side effects
AU - Mizutani, Sayaka
AU - Pauwels, Edouard
AU - Stoven, Véronique
AU - Goto, Susumu
AU - Yamanishi, Yoshihiro
N1 - Funding Information:
Funding: (in part) JSPS International Training Program (ITP) and the Japan Science and Technology Agency. Computational resources were provided by Bioinformatics Center, Institute for Chemical Research, Kyoto University.
PY - 2012/9
Y1 - 2012/9
N2 - Motivation: Identifying the emergence and underlying mechanisms of drug side effects is a challenging task in the drug development process. This underscores the importance of system-wide approaches for linking different scales of drug actions; namely drugprotein interactions (molecular scale) and side effects (phenotypic scale) toward side effect prediction for uncharacterized drugs. Results: We performed a large-scale analysis to extract correlated sets of targeted proteins and side effects, based on the cooccurrence of drugs in protein-binding profiles and side effect profiles, using sparse canonical correlation analysis. The analysis of 658 drugs with the two profiles for 1368 proteins and 1339 side effects led to the extraction of 80 correlated sets. Enrichment analyses using KEGG and Gene Ontology showed that most of the correlated sets were significantly enriched with proteins that are involved in the same biological pathways, even if their molecular functions are different. This allowed for a biologically relevant interpretation regarding the relationship between drug-targeted proteins and side effects. The extracted side effects can be regarded as possible phenotypic outcomes by drugs targeting the proteins that appear in the same correlated set. The proposed method is expected to be useful for predicting potential side effects of new drug candidate compounds based on their protein-binding profiles.
AB - Motivation: Identifying the emergence and underlying mechanisms of drug side effects is a challenging task in the drug development process. This underscores the importance of system-wide approaches for linking different scales of drug actions; namely drugprotein interactions (molecular scale) and side effects (phenotypic scale) toward side effect prediction for uncharacterized drugs. Results: We performed a large-scale analysis to extract correlated sets of targeted proteins and side effects, based on the cooccurrence of drugs in protein-binding profiles and side effect profiles, using sparse canonical correlation analysis. The analysis of 658 drugs with the two profiles for 1368 proteins and 1339 side effects led to the extraction of 80 correlated sets. Enrichment analyses using KEGG and Gene Ontology showed that most of the correlated sets were significantly enriched with proteins that are involved in the same biological pathways, even if their molecular functions are different. This allowed for a biologically relevant interpretation regarding the relationship between drug-targeted proteins and side effects. The extracted side effects can be regarded as possible phenotypic outcomes by drugs targeting the proteins that appear in the same correlated set. The proposed method is expected to be useful for predicting potential side effects of new drug candidate compounds based on their protein-binding profiles.
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U2 - 10.1093/bioinformatics/bts383
DO - 10.1093/bioinformatics/bts383
M3 - Article
C2 - 22962476
AN - SCOPUS:84866460840
VL - 28
SP - i522-i528
JO - Bioinformatics
JF - Bioinformatics
SN - 1367-4803
IS - 18
M1 - bts383
ER -