Molecular Recognition in Ligand–Protein Binding - Drug Design and Discovery - page 15

1 Molecular Recognition

in Ligand-Protein Binding

Tommy Liljefors

CONTENTS
1.1

Introduction ........................................................................................................................... 15

1.2 Determination of the Afi nity—The Total Strength of the Ligand-Protein Interaction ...... 16

1.3 Partitioning of Δ G ................................................................................................................. 18

1.3.1 Δ G transl+rot —The Freezing of the Overall Molecular Motion.................................... 18

1.3.2 Δ G conf —Conformational Changes of Ligand and Receptor .................................... 19

1.3.3 Δ G polar —Electrostatic Interactions and Hydrogen Bonding .................................... 21

1.3.3.1 Hydrogen Bonds ....................................................................................... 21
1.3.3.2 Polar Interactions Involving Aromatic Ring Systems.............................. 23

1.3.4 Δ G hydrophob —The Hydrophobic Effect....................................................................... 24

G vdW —Attractive and Repulsive vdW Interactions ............................................... 25
Further Readings.............................................................................................................................. 26

1.3.5 Δ

1.1 INTRODUCTION
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 under-
standing of the basic principles of molecular recognition is essential for students as well as practi-
tioners 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 i rst 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 i t 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 oversimplii cation of the properties of ligand-protein recogni-
tion. 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 i t 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 i t. Ligands are in general l exible and may change their shape (conformation)

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