The Origin Of Stereospecificity In Molecular Recognition

The lock-and-key hypothesis proposed by Fischer in 1896 was the first attempt to explain the complementarity between a substrate's shape and an enzyme's active site (see also Section 1.1). Koshland's later hypothesis allowed the enzyme to change its shape to accommodate the binding of the substrate (induced fit model). Now we know that both the substrate and the enzyme can change conformation to some extent to ensure optimal binding. Although proposed for enzymes, these models can also be used as the basis to explain drug-receptor interactions.

Receptors (like enzymes) are made up of amino acids, all of which apart from glycine are chiral. The interaction of chiral drugs with receptors would be expected to be enantioselective (i.e., one enantiomer binds with higher affinity than the other). In order to explain the stereoselective action of drugs on receptors, the three-point receptor theory was proposed (Figure 5.5). In this theory only d d d

FIGURE 5.5 The three-point receptor theory. Only one enantiomer can form the three correct interactions with points A', B', and C on the receptor.

FIGURE 5.5 The three-point receptor theory. Only one enantiomer can form the three correct interactions with points A', B', and C on the receptor.

one enantiomer has the optimal spatial disposition of the three groups A, B, and C to interact with the complementary sites on the receptor. Interactions (possibly more than three) could be ionic, hydrophobic, steric, or hydrogen bonding. Although the three-point receptor theory is simplistic, it has also been used successfully to understand chromatographic resolution of mixtures of enantiomers on chiral stationary phases (CSPs), which can be thought of as artificial receptors (see Section 5.5.2).

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