Abstract
BackgroundBiologists generally interrogate genomics data using web-based genome browsers that have limited analytical potential. New generation genome browsers such as the Integrated Genome Browser (IGB) have largely overcome this limitation and permit customized analyses to be implemented using plugins. We illustrate the use of a plugin for IGB that exploits advanced visualization techniques to integrate the analysis of genomics data with network and structural approaches.ResultsWe show how visualization technologies that combine both genomics and network biology can facilitate the selection of the key amino acid contacts from protein-protein and protein-drug interactions. Starting from the MDM2-P53 interaction, which is a high-value target for cancer therapy, and Nutlin, the parent small molecule of an MDM2 antagonist that is currently in clinical trials, we show that this method can be generalized to analyze how drugs and mutations can interfere with both protein-protein and drug-protein networks. We illustrate this point by two additional use-cases exploring the molecular basis of tamoxifen side effects and of drug resistance in chronic myeloid leukemia patients.ConclusionsCombined network and structure biology approaches provide key insights into both the genetic and the edgetic roles of variants in diseases. 3D interactomes facilitate the identification of disease-relevant interactions that can then be specifically targeted by drugs. Recent advances in molecular interaction and structure visualization tools have greatly simplified the mapping of mutated residues to molecular interaction interfaces. Such approaches can now also be integrated with genome visualization tools to enable comparative analyses of interaction contacts.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-0908-x) contains supplementary material, which is available to authorized users.
Highlights
Biologists generally interrogate genomics data using web-based genome browsers that have limited analytical potential
We have recently developed a plugin for Integrated Genome Browser (IGB) [9] that uses advanced visualization techniques to integrate the analysis of genomics data with network and structural biology approaches [10]
We compared the interfaces in proteinprotein interaction (PPI) structures to the interfaces of protein-ligand interactions (PLIs)
Summary
Biologists generally interrogate genomics data using web-based genome browsers that have limited analytical potential. Network and structural biology criteria must be applied to candidate genes in order to pinpoint their contribution to the development of cancer-specific phenotypic traits and to evaluate their druggability. In general terms, the former can be evaluated by studying the connectivity of candidate genes with bona-fide cancer genes in proteinprotein interaction (PPI) networks, while the latter can be deduced from structural information on the protein of interest. The second class of PPIs has sparked particular interest due to the presence of binding pockets and hotspot amino acids that can be identified by experimental and computational methods, and whose function can be disrupted by relatively small compounds developed using traditional medicinal chemistry [6]. Computational tools facilitating the mapping of mutations identified in genomic screens to protein structures are expected to be of considerable help in identifying hotspots
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