Hit me with your best shot: Integrated hit discovery for the next generation of drug targets

•Identifying good-quality start points is essential for small-molecule drug discovery.•There are an increasing number of challenging targets entering drug discovery portfolios.•Many different screening paradigms might be used to attempt to identify hits.•Combining these appropriately for each new target allows an integrated strategy to facilitate high-quality hit identification. Identification of high-quality hit chemical matter is of vital importance to the success of drug discovery campaigns. However, this goal is becoming ever harder to achieve as the targets entering the portfolios of pharmaceutical and biotechnology companies are increasingly trending towards novel and traditionally challenging to drug. This demand has fuelled the development and adoption of numerous new screening approaches, whereby the contemporary hit identification toolbox comprises a growing number of orthogonal and complementary technologies including high-throughput screening, fragment-based ligand design, affinity screening (affinity-selection mass spectrometry, differential scanning fluorimetry, DNA-encoded library screening), as well as increasingly sophisticated computational predictive approaches. Herein we describe how an integrated strategy for hit discovery, whereby multiple hit identification techniques are tactically applied, selected in the context of target suitability and resource priority, represents an optimal and often essential approach to maximise the likelihood of identifying quality starting points from which to develop the next generation of medicines.