Abstract

Phenotypic Drug Discovery with Open Source Software Tools

Marc Bickle, Head of Technology Development Studio, Max Planck Institute of Molecular Cell Biology and Genetics

After years of disappointing returns on investing in target drug based drug discovery, the pharmaceutical industry is increasingly turning to phenotypic drug discovery. This approach has the advantage of being target-agnostic and to conduct the search for new therapeutic agents in the physiologically more relevant environment of the cell. While it is true that cells offer physiologically more relevant environments than proteins in test tubes, several challenges need to be addressed to allow phenotypic screening to improve the success rate of the drug discovery pipeline or we face the danger of suffering similar disillusions as with target based drug discovery. Phenotypic assays need to be physiological relevant, the model needs to address a relevant endpoint and a clear strategy for orthogonal assays interrogating various aspects of the pathology needs to be in place. The increase in physiological relevance will be achieved with the adoption of primary cells or differentiated stem cells cultivated in media matching closely the conditions in the human body, physical parameters such as partial gas tension and stiffness of the substrate mimicking the target organ. The nutrient rich, hyper oxygenated cell culture conditions often used in cell culture lead to altered metabolism and transcriptional profiles that will change the response to drugs. Second, cells coexist and communicate in a body, thus efforts should be undertaken to devise screening assays resembling the cellular composition of the organ under study.