Agonist-informed antagonist discovery: Discovery approaches, medicinal chemistry insights, and design boundaries

In ligand optimization and receptor-targeted drug discovery, agonist scaffolds and ligand series often provide valuable starting points for the discovery of antagonists and inverse agonists. Such scaffolds typically possess validated target binding properties and prior functional characterization, enabling researchers to examine how local structural modifications alter ligand efficacy while preserving key binding interactions. Agonist-informed antagonist discovery can arise from the deliberate redesign of known agonist scaffolds, but it can also emerge through functional differentiation observed during structure-activity relationship studies, hit expansion, or analog evaluation. Drawing on representative cases across these discovery approaches, this review identifies three recurring structural factors: disruption of polar interactions, alteration of hydrophobic contacts, and changes in ligand spatial occupancy. On this basis, the review further discusses the core prerequisites and design boundaries that must be considered when evaluating the feasibility of this strategy. Together, these analyses can help medicinal chemists assess the design rationale, application opportunities, and limitations of using agonist scaffolds and ligand information in the discovery of antagonists.