Gaining insight into off-target mediated effects of drug candidates with a comprehensive systems chemical biology analysis.
We present a workflow that leverages data from chemogenomics based target predictions with Systems Biology databases to better understand off-target related toxicities. By analyzing a set of compounds that share a common toxic phenotype and by comparing the pathways they affect with pathways modulated by nontoxic compounds we are able to establish links between pathways and particular adverse effects. We further link these predictive results with literature data in order to explain why a certain pathway is predicted. Specifically, relevant pathways are elucidated for the side effects rhabdomyolysis and hypotension. Prospectively, our approach is valuable not only to better understand toxicities of novel compounds early on but also for drug repurposing exercises to find novel uses for known drugs.
Scheiber
Josef
J
Lead Discovery Informatics and Preclinical Safety Profiling, CPC, Novartis Institutes for Biomedical Research, 250 Massachussetts Avenue, Cambridge, Massachusetts 02139, USA. mail@josef-scheiber.de
Chen
Bin
B
Milik
Mariusz
M
Sukuru
Sai Chetan K
SC
Bender
Andreas
A
Mikhailov
Dmitri
D
Whitebread
Steven
S
Hamon
Jacques
J
Azzaoui
Kamal
K
Urban
Laszlo
L
Glick
Meir
M
Davies
John W
JW
Jenkins
Jeremy L
JL
D001499:Bayes Theorem; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D012206:Rhabdomyolysis / Q000139:chemically induced; D049490:Systems Biology