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Protein–Ligand Interactions as the Basis for Drug Action

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To purposefully design an active substance the following questions must first be answered: How does a drug act anyway? How does Aspirin® relieve headaches? Why do β-blockers lower blood pressure? Where does a calcium channel blocker act? How does cocaine work? How do sulfonamides prevent the proliferation of bacterial pathogens? An active substance must bind to a very special target molecule in the body to exert its pharmacological action. Usually this is a protein, but nucleic acids in the form of RNA and DNA can also be target structures for active molecules. An important prerequisite for the binding is that the active substance has the correct size and shape to fit into a cavity on the surface of the protein, a binding pocket, as well as possible. Furthermore, it is also necessary that the surface properties of ligand and protein fit together so that the specific interactions can form. In 1894, Emil Fischer compared the exact fit of a substrate for the catalytic center of an enzyme to the picture of a lock and key. In 1913, Paul Ehrlich formulated the Corpora non agunt nisi fixata, which literally translated means “bodies do not act if they are not bound.” With this he wanted to express that drugs that are meant to kill bacteria or parasites must be “fixed,” that is, bound by certain structures. Both concepts form the starting point for rational drug research. In the broadest sense, they are valid even today. After being taken, a drug must arrive at its target tissue and enter into interactions with biological macromolecules there. Specific active substances have a high affinity to a binding site on these macromolecules and are adequately selective. It is only in this way that the desired biological effect can be deployed without extensive side effects.


  • Binding Affinity
  • Binding Pocket
  • Ligand Complex
  • Ligand Interaction
  • Residual Mobility

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  • DOI: 10.1007/978-3-642-17907-5_4
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Klebe, G. (2013). Protein–Ligand Interactions as the Basis for Drug Action. In: Klebe, G. (eds) Drug Design. Springer, Berlin, Heidelberg.

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