Natural Products Beyond Inhibition: A Mechanistic Framework Spanning Pockets, Interfaces, and Kinetic Barriers

Natural products display exceptional chemical diversity and a broad range of mechanisms of action that are not adequately captured by traditional classifications based on target class, pharmacological phenotype, or chemical scaffold. Such classification schemes often lead to fragmented understanding of mechanisms of action, obscuring the unified principles underlying different target systems while failing to recognize the stage-dependent mechanisms exhibited by the same molecule in varying contexts. Here, we propose a unified “space–interface–time” framework to classify the mechanisms of action by examining the physical principles through which natural products reshape the functions of different biomolecules. Within this framework for unifying the classification of natural product mechanisms of action, geometry-driven binding site occupancy and conformational constraints are assigned to the spatial dimension; induction or stabilization of multicomponent complexes and kinetic regulation of state lifetimes are assigned to the interfacial and temporal dimensions, respectively. Finally, we discuss the conceptual and technical challenges of bridging static structural snapshots with dynamic in vivo pharmacology, and highlight emerging opportunities offered by time-resolved structural methods and the integration of molecular dynamics, machine learning, and biophysical workflows for mechanism-guided drug discovery.