Structure-Based Design for Medicinal Chemists
Structure-based design is an established part of the toolbox used to discover drugs, with several marketed drugs and many others in development which trace their lineage to some aspects of structure-based design. Structure-based design is qualitative and empirical. Computational methods help guide design and are improving, but they are still seldom accurate enough to quantitatively predict activity. We summarize the history and progress of structure-based design, forces that drive protein–ligand binding, preferred intermolecular interactions and small molecule conformations, how to visualize and model protein–ligand interactions, and describe a hypothesis-based approach to structure-based design.