With the advent of high-throughput technologies leading to big data generation, increasing number of gene signatures are being published to predict various features of diseases such as prognosis and patient survival. However, to use these signatures for identifying therapeutic targets, use of additional bioinformatic tools is indispensible part of research. Here, we have generated a pipeline comprised of nearly 15 bioinformatic tools and enrichment statistical methods to propose and validate a drug combination strategy from already approved drugs and present our approach using published pan-cancer epithelial-mesenchymal transition (EMT) signatures as a case study. We observed that histone deacetylases were critical targets to tune expression of multiple epithelial versus mesenchymal genes. Moreover, SRC and IKBK were the principal intracellular kinases regulating multiple signaling pathways. To confirm the anti-EMT efficacy of the proposed target combination in silico, we validated expression of targets in mesenchymal versus epithelial subtypes of ovarian cancer. Additionally, we inhibited the pinpointed proteins in vitro using an invasive lung cancer cell line. We found that whereas low-dose mono-therapy failed to limit cell dispersion from collagen spheroids in a microfluidic device as a metric of EMT, the combination fully inhibited dissociation and invasion of cancer cells toward cocultured endothelial cells. Given the approval status and safety profiles of the suggested drugs, the proposed combination set can be considered in clinical trials.

MOTIVATION: Centrality analysis involves a series of ambiguities in that there are numerous well-known centrality measures with differing algorithms for establishing which nodes in a network are essential. There is no clearly preferred measure or means of deciding which measure is most germane to a given network with respect to node essentiality vis-à-vis topological features. Our aim here was to develop an instrument that enables comparisons among potentially appropriate centrality measures to be made with respect to network structure and thereby to support the identification of the most informative measure according to dimensional reduction methods. METHODS: The Central Informative Nodes in Network Analysis (CINNA) package introduced herein gathers all required functions for centrality analysis in weighted/unweighted and directed/undirected networks. Then, it compares, assorts and visualizes centrality measures to select which best describes the node importance. AVAILABILITY AND IMPLEMENTATION: CINNA is available in CRAN, including a tutorial. URL: https://cran.r-project.org/web/packages/CINNA/index.html.

BACKGROUND: Reconstruction of protein-protein interaction networks (PPIN) has been riddled with controversy for decades. Particularly, false-negative and -positive interactions make this progress even more complicated. Also, lack of a standard PPIN limits us in the comparison studies and results in the incompatible outcomes. Using an evolution-based concept, i.e. interolog which refers to interacting orthologous protein sets, pave the way toward an optimal benchmark. RESULTS: Here, we provide an R package, IMMAN, as a tool for reconstructing Interolog Protein Network (IPN) by integrating several Protein-protein Interaction Networks (PPINs). Users can unify different PPINs to mine conserved common networks among species. IMMAN is designed to retrieve IPNs with different degrees of conservation to engage prediction analysis of protein functions according to their networks. CONCLUSIONS: IPN consists of evolutionarily conserved nodes and their related edges regarding low false positive rates, which can be considered as a gold standard network in the contexts of biological network analysis regarding to those PPINs which is derived from.

BACKGROUND: Evaluation of protein structure is based on trustworthy potential function. The total potential of a protein structure is approximated as the summation of all pair-wise interaction potentials. Knowledge-based potentials (KBP) are one type of potential functions derived by known experimentally determined protein structures. Although several KBP functions with different methods have been introduced, the key interactions that capture the total potential have not studied yet. RESULTS: In this study, we seek the interaction types that preserve as much of the total potential as possible. We employ a procedure based on the principal component analysis (PCA) to extract the significant and key interactions in native protein structures. We call these interactions as principal interactions and show that the results of the model that considers only these interactions are very close to the full interaction model that considers all interactions in protein fold recognition. In fact, the principal interactions maintain the discriminative power of the full interaction model. This method was evaluated on 3 KBPs with different contact definitions and thresholds of distance and revealed that their corresponding principal interactions are very similar and have a lot in common. Additionally, the principal interactions consisted of 20 % of the full interactions on average, and they are between residues, which are considered important in protein folding. CONCLUSIONS: This work shows that all interaction types are not equally important in discrimination of native structure. The results of the reduced model based on principal interactions that were very close to the full interaction model suggest that a new strategy is needed to capture the role of remaining interactions (non-principal interactions) to improve the power of knowledge-based potential functions.

Network pharmacology elucidates the relationship between drugs and targets. As the identified targets for each drug increases, the corresponding drug-target network (DTN) evolves from solely reflection of the pharmaceutical industry trend to a portrait of polypharmacology. The aim of this study was to evaluate the potentials of DrugBank database in advancing systems pharmacology. We constructed and analyzed DTN from drugs and targets associations in the DrugBank 4.0 database. Our results showed that in bipartite DTN, increased ratio of identified targets for drugs augmented density and connectivity of drugs and targets and decreased modular structure. To clear up the details in the network structure, the DTNs were projected into two networks namely, drug similarity network (DSN) and target similarity network (TSN). In DSN, various classes of Food and Drug Administration-approved drugs with distinct therapeutic categories were linked together based on shared targets. Projected TSN also showed complexity because of promiscuity of the drugs. By including investigational drugs that are currently being tested in clinical trials, the networks manifested more connectivity and pictured the upcoming pharmacological space in the future years. Diverse biological processes and protein-protein interactions were manipulated by new drugs, which can extend possible target combinations. We conclude that network-based organization of DrugBank 4.0 data not only reveals the potential for repurposing of existing drugs, also allows generating novel predictions about drugs off-targets, drug-drug interactions and their side effects. Our results also encourage further effort for high-throughput identification of targets to build networks that can be integrated into disease networks.

BACKGROUND: In the field of network science, exploring principal and crucial modules or communities is critical in the deduction of relationships and organization of complex networks. This approach expands an arena, and thus allows further study of biological functions in the field of network biology. As the clustering algorithms that are currently employed in finding modules have innate uncertainties, external and internal validations are necessary. METHODS: Sequence and network structure alignment, has been used to define the Interlog Protein Network (IPN). This network is an evolutionarily conserved network with communal nodes and less false-positive links. In the current study, the IPN is employed as an evolution-based benchmark in the validation of the module finding methods. The clustering results of five algorithms; Markov Clustering (MCL), Restricted Neighborhood Search Clustering (RNSC), Cartographic Representation (CR), Laplacian Dynamics (LD) and Genetic Algorithm; to find communities in Protein-Protein Interaction networks (GAPPI) are assessed by IPN in four distinct Protein-Protein Interaction Networks (PPINs). RESULTS: The MCL shows a more accurate algorithm based on this evolutionary benchmarking approach. Also, the biological relevance of proteins in the IPN modules generated by MCL is compatible with biological standard databases such as Gene Ontology, KEGG and Reactome. CONCLUSION: In this study, the IPN shows its potential for validation of clustering algorithms due to its biological logic and straightforward implementation.