Structure and organization of drug-target networks: insights from genomic approaches for drug discovery

Abstract

Recent years have seen an explosion in the amount of "omics" data and the integration of several disciplines, which has influenced all areas of life sciences including that of drug discovery. Several lines of evidence now suggest that the traditional notion of "one drug-one protein" for one disease does not hold any more and that treatment for most complex diseases can best be attempted using polypharmacological approaches. In this review, we formalize the definition of a drug-target network by decomposing it into drug, target and disease spaces and provide an overview of our understanding in recent years about its structure and organizational principles. We discuss advances made in developing promiscuous drugs following the paradigm of polypharmacology and reveal their advantages over traditional drugs for targeting diseases such as cancer. We suggest that drug-target networks can be decomposed to be studied at a variety of levels and argue that such network-based approaches have important implications in understanding disease phenotypes and in accelerating drug discovery. We also discuss the potential and scope network pharmacology promises in harnessing the vast amount of data from high-throughput approaches for therapeutic advantage.

Systems and Network-Based Approaches for Personalized Medicine

“…However with recent advances in genetics and our understanding of pharmacological behavior of different drugs, it is evident that genetic variations among individuals lead to differences in response to drugs and most complex multi-gene associated diseases could be treated with different drugs depending on the exact genetic variant responsible for the observed phenotype seen in the population. In addition, conventional medicines which were geared towards avoiding side-affects often result in adverse effects despite extensive engineering and often lack efficacy [5]. All these factors together with the observation that conventional clinical trials usually fail for several newly developed drugs because they take in statistical information about the general population of patients and apply it to the individual, has resulted in the notion of personalized medicine.…”

“…Integration of networks encompassing interactions between different cellular entities can then be studied within the framework of genetic and/or transcriptomic variations responsible for these variations by comparing at different levels; from cells, organs, tissues to individuals to identify the nodes which are responsible for these changes. Detailed changes in cellular phenotype can be quantitatively measured using high content phenotypic screens and hence libraries of small molecules, peptides or poly-nucleotides such as siRNA can be screened to target specific cellular entities that need to be modulated in order to revert the cellular state from a diseased to a healthy one (Figure 1) [5].…”

Human Disease and Drug Pharmacology, Complex as Real Life

“…In this light, it becomes apparent that exquisitely selective drugs designed as "magic bullets" in the frame of the reductionist approach might easily exhibit lower-than-needed efficacy, which might in a great part account for the high attrition figures in clinical trials during the past decades. On the contrary, network pharmacology involving polypharmacological therapeutic interventions that selectively hit multiple relevant protein targets within the pathological network as "magic shotguns", emerges as a realistic alternative drug discovery approach that should derive treatments with greater clinical efficacy [4,5,7,17,19,29,[39][40][41][42][43][44].…”

“…Thus, the one-disease, one-gene, oneprotein, one-drug philosophy constitutes the rational basis of the so-called reductionist approach of drug discovery, which is the most prevailing paradigm of current rational drug design both in pharmaceutical companies and in academy [3]. In the early steps of the drug discovery process the pharmacological profile of new investigational compounds is established by subjecting them to a number of in vitro tests against the particular isolated protein target, considered critical for the disease, that is expected to be hit by the studied compounds, and a number of other isolated related targets that are expected not to be hit by those compounds [3,4].…”

Identifying potential therapeutic targets of a natural product Jujuboside B for insomnia through network pharmacology

“…Identifying drug targets is a critical step in pharmacology. Recent years, network pharmacology has influenced all areas of life sciences including that of drug mechanism and development, new target discovery (Janga, & Tzakos, 2009). Efficient identification of drug targets is one of major challenges for drug discovery and drug development.…”