An industrial perspective on ligand bias in GPCR drug discovery

Since the initial identification of ligand bias in the late 1990s, the possibility of designing new clinical compounds that preferentially target select signalling pathways has been attractive to drug developers. The potential for maximising efficacy and minimising on-target side-effects at early lead optimisation stages could significantly improve the success rate of discovery programmes. However, the search for truly biased ligands poses additional challenges to the considerable existing difficulties facing any lead compound on its route to clinical licensing. As such, despite their potential advantages, the development of biased ligands has been limited within the wider pharmaceutical industry so far. Here, we give our current perspective on the landscape of biased ligand development and an overview of the wider implications that must be considered when entering a biased ligand discovery programme.