title: Distinctive Behaviors of Druggable Proteins in Cellular Networks.
abstract: 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/.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Costas
authors.initials: C
authors.lastname: Mitsopoulos
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Schierz
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Bissan
authors.initials: B
authors.lastname: Al-Lazikani
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D003198:Computer Simulation; D016503:Drug Delivery Systems / Q000379:methods; D055808:Drug Discovery / Q000379:methods; D004360:Drug Therapy, Computer-Assisted / Q000379:methods; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D025941:Protein Interaction Mapping / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins