Polypharmacology prediction: the long road toward comprehensively anticipating small-molecule selectivity to de-risk drug discovery

Introduction: Small molecules often bind to multiple targets, a behavior termed polypharmacology. Anticipating polypharmacology is essential for drug discovery since unknown off-targets can modulate safety and efficacy–profoundly affecting drug discovery success. Unfortunately, experimental methods to assess selectivity present significant limitations and drugs still fail in the clinic due to unanticipated off-targets. Computational methods are a cost-effective, complementary approach to predict polypharmacology. Areas covered: This review aims to provide a comprehensive overview of the state of polypharmacology prediction and discuss its strengths and limitations, covering both classical cheminformatics methods and bioinformatic approaches. The authors review available data sources, paying close attention to their different coverage. The authors then discuss major algorithms grouped by the types of data that they exploit using selected examples. Expert opinion: Polypharmacology prediction has made impressive progress over the last decades and contributed to identify many off-targets. However, data incompleteness currently limits most approaches to comprehensively predict selectivity. Moreover, our limited agreement on model assessment challenges the identification of the best algorithms–which at present show modest performance in prospective real-world applications. Despite these limitations, the exponential increase of multidisciplinary Big Data and AI hold much potential to better polypharmacology prediction and de-risk drug discovery.