Where should surface plasmon resonance go next? Toward mechanistic drug discovery

Surface plasmon resonance (SPR) has become a central method for quantifying biomolecular interactions through real-time measurements of affinity, association and dissociation rate constants, residence time, and binding capacity. However, these parameters do not necessarily identify the molecular state responsible for biological activity. This Perspective examines how SPR can move beyond binary interaction analysis toward a more mechanistic description of molecular recognition. We discuss how assay design, surface presentation, membrane context, multicomponent formats, and computational analysis have already expanded the biological questions accessible to SPR. We then focus on the next information layer: molecular state. Experimental studies show that conformational rearrangements can contribute directly to SPR responses and that complementary readouts, including fluorescence, surface-enhanced Raman scattering, and label-enhanced detection, can provide state-sensitive, chemical, or assembly-specific information during the interaction itself. We propose that future SPR experiments should integrate interaction kinetics with molecular state, assembly, environment, and functional consequence along a common time axis. The goal is not to replace affinity and kinetics, but to extend their interpretation. The next evolution of SPR lies in connecting quantitative molecular interaction analysis with the molecular states and assemblies that contribute to biological and pharmacological mechanism. This framework could improve mechanistic decision-making across modern drug discovery.