Network Based Drug Discovery: Coupling Network Pharmacology with Phenotypic Screening for Neuronal Excitability

Publication date: Available online 18 July 2018Source: Journal of Molecular BiologyAuthor(s): Ben Sidders, Anna Karlsson, Linda Kitching, Rubben Torella, Paul Karila, Anne PhelanAbstractDiseases such as chronic pain with complex aetiologies 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

Source: Journal of Molecular Biology - July 18, 2018 Category: Molecular Biology Source Type: research