Network Neighbors of Drug Targets Contribute to Drug Side-Effect Similarity

Abstract

In pharmacology, it is essential to identify the molecular mechanisms of drug action in order to understand adverse side effects. These adverse side effects have been used to infer whether two drugs share a target protein. However, side-effect similarity of drugs could also be caused by their target proteins being close in a molecular network, which as such could cause similar downstream effects. In this study, we investigated the proportion of side-effect similarities that is due to targets that are close in the network compared to shared drug targets. We found that only a minor fraction of side-effect similarities (5.8 %) are caused by drugs targeting proteins close in the network, compared to side-effect similarities caused by overlapping drug targets (64%). Moreover, these targets that cause similar side effects are more often in a linear part of the network, having two or less interactions, than drug targets in general. Based on the examples, we gained novel insight into the molecular mechanisms of side effects associated with several drug targets. Looking forward, such analyses will be extremely useful in the process of drug development to better understand adverse side effects.

Physiological regulatory networks: ecological roles and evolutionary constraints

“…We might identify key molecules within PRN structure (integrators or otherwise) that facilitate or constrain evolutionary change. Such approaches are being used in pharmacology to identify key targets for drug discovery [51] and their potential side-effects [52]. An ecological example would be to ask what bird lineages were able to successfully diversify from tropical habitat into temperate.…”

Suberoylanilide Hydroxamic Acid (SAHA)-Induced Dynamics of a Human Histone Deacetylase Protein Interaction Network

“…Drugs often interact with a number of additional proteins beyond their primary targets (1)(2)(3). Therefore, drugs have effects on multiple pathways beyond altering the activity of a single protein.…”

“…Therefore, drugs have effects on multiple pathways beyond altering the activity of a single protein. Two histone deacetylase (HDAC) 1 inhibitors approved by the U.S. Food and Drug Administration, suberoylanilide hydroxamic acid (SAHA) and depsipeptide (Romidepsin), are used for the treatment of advanced and refractory cutaneous T-cell lymphoma in patients with progressive, persistent, or recurrent disease (4). SAHA has the permeability to cross the blood-brain barrier and cause biological responses in the mouse brain, making it a preferred candidate drug for testing in the central nervous system (5,6).…”

Protein-Protein Interaction Networks: Structures, Evolution, and Application to Drug Design

“…Recently, Brouwers et al (2011) investigated how side effect similarities of targets depend on their closeness in the human PIN. They found that a certain number of pairs of two drugs without common targets show similar side effects, when they are close in the human PIN.…”

“…With recent influx of information of biological networks, especially the human interactome, analyses like Brouwers et al (2011) or Wang et al (2011 can be refined and adapted to infer still unknown adverse side effects of drugs and to predict possible target genes. Indeed, by integrating information of the human PIN with similarities between two genes (e.g., GO semantic and sequence similarity) and those between two drugs (e.g., chemical and drug therapeutic similarity), several recent researches attempted to develop a method to predict possible targets for therapeutic drugs (Zhao & Li 2010, Perlman et al 2011).…”