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2018 ; 9
(ä): 151
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Exploration of the Anti-Inflammatory Drug Space Through Network Pharmacology:
Applications for Drug Repurposing
#MMPMID29545755
de Anda-Jáuregui G
; Guo K
; McGregor BA
; Hur J
Front Physiol
2018[]; 9
(ä): 151
PMID29545755
show ga
The quintessential biological response to disease is inflammation. It is a driver
and an important element in a wide range of pathological states. Pharmacological
management of inflammation is therefore central in the clinical setting.
Anti-inflammatory drugs modulate specific molecules involved in the inflammatory
response; these drugs are traditionally classified as steroidal and non-steroidal
drugs. However, the effects of these drugs are rarely limited to their canonical
targets, affecting other molecules and altering biological functions with
system-wide effects that can lead to the emergence of secondary therapeutic
applications or adverse drug reactions (ADRs). In this study, relationships among
anti-inflammatory drugs, functional pathways, and ADRs were explored through
network models. We integrated structural drug information, experimental
anti-inflammatory drug perturbation gene expression profiles obtained from the
Connectivity Map and Library of Integrated Network-Based Cellular Signatures,
functional pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and
Reactome databases, as well as adverse reaction information from the U.S. Food
and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The network
models comprise nodes representing anti-inflammatory drugs, functional pathways,
and adverse effects. We identified structural and gene perturbation similarities
linking anti-inflammatory drugs. Functional pathways were connected to drugs by
implementing Gene Set Enrichment Analysis (GSEA). Drugs and adverse effects were
connected based on the proportional reporting ratio (PRR) of an adverse effect in
response to a given drug. Through these network models, relationships among
anti-inflammatory drugs, their functional effects at the pathway level, and their
adverse effects were explored. These networks comprise 70 different
anti-inflammatory drugs, 462 functional pathways, and 1,175 ADRs. Network-based
properties, such as degree, clustering coefficient, and node strength, were used
to identify new therapeutic applications within and beyond the anti-inflammatory
context, as well as ADR risk for these drugs, helping to select better
repurposing candidates. Based on these parameters, we identified naproxen,
meloxicam, etodolac, tenoxicam, flufenamic acid, fenoprofen, and nabumetone as
candidates for drug repurposing with lower ADR risk. This network-based analysis
pipeline provides a novel way to explore the effects of drugs in a therapeutic
space.