Drug-target interactions that connects with causal genes for another disease may, therefore, be helpful for drug repositioning. In addition, by revealing new relationships of an existing target with another disease, a drug may be repositioned. Some methods utilize drug-induced transcriptional profiles for drug repurposing. For example, to pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, Lamb and colleagues have created a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules 95. By using pattern matching methods to mine the data, this Connectivity Map (also known as CMap) resource can be used to find connections among small molecules sharing a mechanism of action, or structural or physiological processes. One of the successful applications of CMap for drug repositioning was conducted by Iorio and colleagues 96. In this study, an automatic approach that exploits similarity in gene expression profiles following drug treatment was developed to predict similarities in drug effect and mode of action. A drug network displaying similarities between pair of drugs was next constructed and partitioned into groups of densely interconnected nodes. Based on this network, Iorio and colleagues correctly predicted the mode of action for nine anticancer compounds and discovered an unreported effect for a well-known drug, fasudil (a Rhokinase inhibitor). Using CMap data, a large set of drug-induced transcriptional modules was identified in another study 97. By utilizing conserved and cell-type-specific drug-induced modules, the investigators further predicted gene functions of some regulators and revealed new mechanisms-of-action for existing drugs, providing a starting point for drug repositioning. Examples mentioned above demonstrate that drug-induced high-throughput gene expression profiles combined with proper computational methods are very useful for drug combination and drug repositioning. In addition to transcriptional profiles, drug-target networks and protein-protein interaction networks have been widely utilized for drug target identification 98. Such methods often use node similarity or structural features of biological networks. For example, Keiser and colleagues constructed drug-target networks and used a statistics-based chemoinformatics approach that explores the chemical similarities between drugs and ligand sets to predict thousands of drug-target unanticipated Avermectin B1a price associations 99. Hwang and colleagues developed a novel network metric called bridging centrality to identify bridging nodes critically involved in connecting modular subregions of a protein interaction network. They GW9662 site showed that bridging nodes are promising drug targets from the standpoints of efficacy and side effects 100. Metabolite profiles and metabolic networks have been used in drug discovery studies, as well 101. In addition, some methods have been developed for predicting the adverse side effects of drugs using network models 102, 103.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptWiley Interdiscip Rev Syst Biol Med. Author manuscript; available in PMC 2016 July 01.Wang et al.PagePERSONALIZED MEDICINEPersonalized medicine, a medical model of customized healthcare in which an individual patient is provided with treatments tailored to his/her genomic makeup, has been discussed for many years. Advances in next generat.Drug-target interactions that connects with causal genes for another disease may, therefore, be helpful for drug repositioning. In addition, by revealing new relationships of an existing target with another disease, a drug may be repositioned. Some methods utilize drug-induced transcriptional profiles for drug repurposing. For example, to pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, Lamb and colleagues have created a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules 95. By using pattern matching methods to mine the data, this Connectivity Map (also known as CMap) resource can be used to find connections among small molecules sharing a mechanism of action, or structural or physiological processes. One of the successful applications of CMap for drug repositioning was conducted by Iorio and colleagues 96. In this study, an automatic approach that exploits similarity in gene expression profiles following drug treatment was developed to predict similarities in drug effect and mode of action. A drug network displaying similarities between pair of drugs was next constructed and partitioned into groups of densely interconnected nodes. Based on this network, Iorio and colleagues correctly predicted the mode of action for nine anticancer compounds and discovered an unreported effect for a well-known drug, fasudil (a Rhokinase inhibitor). Using CMap data, a large set of drug-induced transcriptional modules was identified in another study 97. By utilizing conserved and cell-type-specific drug-induced modules, the investigators further predicted gene functions of some regulators and revealed new mechanisms-of-action for existing drugs, providing a starting point for drug repositioning. Examples mentioned above demonstrate that drug-induced high-throughput gene expression profiles combined with proper computational methods are very useful for drug combination and drug repositioning. In addition to transcriptional profiles, drug-target networks and protein-protein interaction networks have been widely utilized for drug target identification 98. Such methods often use node similarity or structural features of biological networks. For example, Keiser and colleagues constructed drug-target networks and used a statistics-based chemoinformatics approach that explores the chemical similarities between drugs and ligand sets to predict thousands of drug-target unanticipated associations 99. Hwang and colleagues developed a novel network metric called bridging centrality to identify bridging nodes critically involved in connecting modular subregions of a protein interaction network. They showed that bridging nodes are promising drug targets from the standpoints of efficacy and side effects 100. Metabolite profiles and metabolic networks have been used in drug discovery studies, as well 101. In addition, some methods have been developed for predicting the adverse side effects of drugs using network models 102, 103.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptWiley Interdiscip Rev Syst Biol Med. Author manuscript; available in PMC 2016 July 01.Wang et al.PagePERSONALIZED MEDICINEPersonalized medicine, a medical model of customized healthcare in which an individual patient is provided with treatments tailored to his/her genomic makeup, has been discussed for many years. Advances in next generat.
