Screening chemicals for receptor-mediated toxicological/ pharmacological endpoints: Using public data to build screening tools within KNIME

Abstract

Assessing chemical compounds for pharmacological and toxicological properties is of great interest for industry and regulatory bodies. A straightforward approach to build screening tools for receptor-mediated effects is introduced. Solely open source software and open access databases were used. As a pharmacologically and toxicologically relevant target, the retinoic acid receptor (RAR) was chosen. RAR agonists are used in the treatment of certain dermal diseases and specific types of cancer. Chronically administered, there is strong evidence for RAR agonists causing hepatosteatosis and liver injury. After compiling information on ligand-protein-interactions, common substructures and physico-chemical properties of ligands, a rule-based screening workflow was built within KNIME. Structural information was coded in SMARTS. The workflow was tested on two datasets: One with RAR agonists exclusively and another large, chemically diverse dataset containing only few RAR agonists. In conclusion a screening tool for RAR agonists was developed. Possible modifications and applications of screening workflows, dependent on their purpose, were discussed thoroughly.