Network-Based Drug Discovery: Coupling Network Pharmacology with Phenotypic Screening for Neuronal Excitability. Issue 18 (14th September 2018)

• Record Type: Journal Article
• Authors: Sidders, Ben; Karlsson, Anna; Kitching, Linda; Torella, Rubben; Karila, Paul; Phelan, Anne
• Is Part Of: Journal of molecular biology. Volume 430:Issue 18(2018)Part A
• Page Start: 3005
• Page End: 3015
• Publication Date: 2018-09-14
• Subjects: network-based drug discovery -- neuroscience -- pain -- drug repurposing; EFS electric field stimulation -- DRG dorsal root ganglion -- PSA polar surface area -- PPIs protein–protein interactions -- NGF nerve growth factor; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2018.07.016
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: Diseases such as chronic pain with complex etiologies are unlikely to respond to single, target-specific therapeutics but rather require intervention at multiple points within a perturbed disease system. Such approaches are being enabled by the rise of computational methods to identify key points of intervention and by new screening techniques that focus on a relevant condition or phenotype, rather than a specific target. Here we apply an in silico network pharmacology approach to identify small-molecule compounds with the potential to selectively disrupt the structure of a chronic-pain specific disease network, which we validate using a novel phenotypic screen that recapitulates key aspects of neuronal and pain biology by measuring changes in neuronal excitability in native sensory neurons. The combination of network pharmacology with a phenotypic screen is a powerful approach; we show that hit rates increase from 26% to 42%. This represents a rational approach to the discovery of compounds with a poly-pharmacology based therapeutic value, which will be vital for the discovery of treatments for complex disease. Graphical abstract: Highlights: A novel phenotypic screen for neuronal excitability recapitulates key aspects of chronic pain. Network pharmacology based predictions of drug activity in a disease-specific protein interaction network identify effective compounds (AUC 0.77) Our network-based approach significantly increases hit rates compared to manual compound selection based on known primary pharmacology.