The Polypharmacology Gap Between Chemical Biology and Drug Discovery

Abstract

In recent years, it has become increasingly apparent that small-molecule drugs tend to interact with more than one protein, a behaviour commonly referred to as polypharmacology, which is increasingly being exploited in drug discovery. However, in chemical biology, chemical probes are assumed to be completely selective against their primary target and their utility is believed to rely precisely on this selectivity. In this chapter, we first review the use of computational methods to predict polypharmacology. Next, the impact of unknown chemical probe polypharmacology in chemical biology and follow-up drug discovery is presented using PARP inhibitors as a case study. Finally, a large collection of chemical probes is used to demonstrate that polypharmacology to non-obvious off-targets is also common among chemical probes and that computational systems pharmacology methods are a cost effective de-risking strategy in chemical biology. Overall, a more comprehensive and systems approach to chemical biology and drug discovery facilitated by the use of computational methods is urgently needed to bridge both disciplines and advance towards a more solid knowledge-base in biology that can be safely translated into safer, more effective, small-molecule therapeutics.