Molecular recognition is a basic feature of virtually all biological phenomena. In the case of ligand-protein binding it can be described as the ability of a ligand and a protein (an enzyme or a receptor) to form a "noncovalent" complex. Covalent binding between a ligand and a protein occurs, but is much less common and a discussion of such binding is outside the scope of this chapter. An understanding of the basic principles of molecular recognition is essential for students as well as practitioners of medicinal chemistry. It provides an ability to interpret experimental ligand-binding data and gives an understanding of structure-activity relationships in terms of physical forces acting in the ligand-protein binding process. Such an understanding is a prerequisite for the rational design of new ligands—new potential drug molecules.

The first attempt to understand the basic properties of ligand-protein recognition was formulated in the "lock-and-key" hypothesis by Emil Fischer (1894). A cartoon illustration of this hypothesis is given in Figure 1.1a. The essence of the hypothesis is that the protein (in this case, an enzyme) and the ligand must fit together like a lock and a key in order to initiate a chemical reaction (i.e., enzymatic catalysis). The ligand as well as the protein in this hypothesis is considered to be rigid. Although the lock-and-key hypothesis has been useful for generations of medicinal chemists, it gradually became clear that it is an oversimplification of the properties of ligand-protein recognition. For instance, noncompetitive enzyme inhibition could not be explained by the hypothesis and the fact that some enzymes are highly selective, whereas other enzymes may interact with several structurally different substrates could not be understood. This led Koshland (1958) to introduce the "induced fit theory" (Figure 1.1b) in which the interaction between a ligand and a protein could be described as "a hand in a glove," where the hand and the glove both adjust their shapes in order to provide an optimal fit. Ligands are in general flexible and may change their shape (conformation)


FIGURE 1.1 (a) Lock-and-key and (b) induced fit hypotheses.

by rotation about single bonds. In the protein, side-chain conformations as well as the backbone conformation may adjust to optimize the ligand-protein interaction. The rapidly increasing number of crystallographically determined 3D structures of proteins and ligand-protein complexes give strong support to the induced fit hypothesis and this hypothesis is today generally accepted by the scientific community.

Studying an x-ray structure of a ligand-protein complex as visualized by modern computer graphics hardware and software is fascinating and many useful details about ligand-protein interactions can be learned from that. However, a study of a ligand-protein complex alone tells only a part of the story of ligand-protein interactions. For instance, it does not give much information about the strengths of the observed interactions. The purpose of this chapter is to discuss and give examples of ligand-protein interactions in terms of basic physical chemistry. This chapter focuses on the understanding of the type and magnitude of different contributions to the strength of the ligand-protein binding. This may provide answers to questions about what to expect in terms of affinity for a given drug if, for instance, a substituent in this drug is replaced by another one. It also provides a framework for other chapters in this book in which structure-affinity relationships are being discussed.

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