Functional Polypharmacology in Gene Focused Drug Discovery

Abstract

The disciplines of small molecule drug discovery and chemical genetics are highly related in that they both study the effect of small molecules on biological systems, but also differ in intention. Drug discovery aims to find disease mitigating substances, while chemical biology ultimately aims to increase our knowledge of biology. Despite this difference however, both chemical genetics and targeted drug discovery have focused on selectivity of small molecules to assess the quality of their molecules and infer likelihood of success. The logic for pursuing selectivity in chemical genetics is that a truly specific in that it binds to a single protein, the phenotypic changes observed when using this molecule can be attributed to the function of this protein. In this case, selectivity can be seen as a runner-up or best alternative of specificity. In drug discovery, selectivity became key as the practice of targeted drug discovery, which approaches therapeutics from a ‘one disease, one gene, one drug’ angle. In targeted drug discovery, selectivity is regarded as indicative for the likelihood of side-effects associated with therapeutic drugs – the more selective a drug candidate, the lower the likelihood of a no side-effect effective therapeutic. This thesis focuses on various aspects of small molecule selectivity. Throughout the chapters I review how selectivity of small molecules became a concept that was important to medicinal chemists and molecular biologists in drug discovery. I assess the selectivity of currently available small molecules in a data-driven manner. I develop metrics that accurately describe diverse biological properties of small molecules in a data driven fashion and use this to improve compound selection for initial screening of small molecules as well as biological conclusions drawn from these studies. Ultimately, I investigate whether the lack of specificity often found in approved therapeutic drugs could be advantageous to their efficacy for which I compare drug targets that are inhibited concomittedly to the modular patterns in genomic functional redundancy. Lastly, in the final chapter, I propose how the findings described in this thesis can be incorporated in future studies in both chemical genetics and drug discovery.