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

Area of Science:

• Natural Product Chemistry
• Chemical Biology
• Pharmacology

Background:

• Traditional classifications of natural products are limited.
• Existing schemes fragment understanding of mechanisms of action.
• A unified framework is needed to capture diverse molecular interactions.

Purpose of the Study:

• To propose a unified "space-interface-time" framework for classifying natural product mechanisms of action.
• To examine the physical principles governing natural product-biomolecule interactions.
• To bridge static structural data with dynamic in vivo pharmacology.

Main Methods:

• Classifying mechanisms based on spatial, interfacial, and temporal dimensions.
• Analyzing geometry-driven binding site occupancy and conformational constraints (space).
• Investigating induction/stabilization of multicomponent complexes and kinetic regulation (interface and time).

Main Results:

• The proposed framework integrates geometric, kinetic, and dynamic aspects of natural product action.
• Spatial dimension: binding site occupancy and conformational constraints.
• Interfacial and temporal dimensions: complex formation and kinetic regulation.

Conclusions:

• The "space-interface-time" framework offers a unified approach to natural product mechanism classification.
• Emerging technologies like time-resolved structural methods and integrated computational workflows are crucial.
• This framework facilitates mechanism-guided drug discovery by providing a comprehensive understanding of molecular interactions.