Distinctive Behaviors of Druggable Proteins in Cellular Networks.
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Date
2015-12-23Author
Mitsopoulos, C
Schierz, AC
Workman, P
Al-Lazikani, B
Type
Journal Article
Metadata
Show full item recordAbstract
The interaction environment of a protein in a cellular network is important in defining the role that the protein plays in the system as a whole, and thus its potential suitability as a drug target. Despite the importance of the network environment, it is neglected during target selection for drug discovery. Here, we present the first systematic, comprehensive computational analysis of topological, community and graphical network parameters of the human interactome and identify discriminatory network patterns that strongly distinguish drug targets from the interactome as a whole. Importantly, we identify striking differences in the network behavior of targets of cancer drugs versus targets from other therapeutic areas and explore how they may relate to successful drug combinations to overcome acquired resistance to cancer drugs. We develop, computationally validate and provide the first public domain predictive algorithm for identifying druggable neighborhoods based on network parameters. We also make available full predictions for 13,345 proteins to aid target selection for drug discovery. All target predictions are available through canSAR.icr.ac.uk. Underlying data and tools are available at https://cansar.icr.ac.uk/cansar/publications/druggable_network_neighbourhoods/.
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Subject
Humans
Neoplasms
Neoplasm Proteins
Antineoplastic Agents
Drug Delivery Systems
Drug Therapy, Computer-Assisted
Protein Interaction Mapping
Signal Transduction
Algorithms
Models, Biological
Computer Simulation
Drug Discovery
Molecular Targeted Therapy
Research team
Computational Biology and Chemogenomics
Language
eng
Date accepted
2015-10-13
License start date
2015-12-23
Citation
PLoS computational biology, 2015, 11 (12), pp. e1004597 - ?
Publisher
PUBLIC LIBRARY SCIENCE