The identification of novel therapeutic targets for disease intervention has become paramount in the current drug discovery environment.  Phenotypic screening aims to identify new targets by screening chemical matter against cells or organisms that model a diseased state as genuinely as possible.  In the current screening paradigm, emphasis has been placed on the translatability of the initial screen, leading to lower throughput, and the need for screening the most meaningful set of compounds upfront, followed by expansion.  A suite of integrated data repositories and tools have been developed to empower phenotypic screening at our company.  A chemogenomics database CHEMGENIE that captures compound-target interactions has been implemented by integrating and harmonizing internal and external data sources.  This allows one to identify the chemical matter that perturbs a target, as well as view the activity profile of a compound against all measured targets.  Based on these activity profiles, an algorithm to identify tool compounds has been designed.  Furthermore, a tool nomination app has been implemented to identify tools via crowd-sourcing. We describe use cases of screening the tool set in phenotypic screens, and the ability to identify targets and pathways that perturb a phenotype through “target enrichment.”  In addition, we describe advances in iterative focused screening (IFS) aimed at identifying as many active chemotypes as possible with the constraints of highly complex and lower throughput phenotypic screens.

Chemical biology informatic approaches to enable high-throughput screening: Focused compounds sets, target enrichment, and hit expansion

253rd National Meeting (2017)

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