Binding site three-point interaction model

The concept of the three-point fit was proposed in 1933 [11]. In this model, stereochemical differences in pharmacological activities were due to the differential binding of enantiomers to a common site on a receptor surface. The three-point interaction model was revisited by Ogston [12]. However, the often-quoted paper is the one from Dalgliesh [13], who invoked a three-point interaction to explain the enantioselective separation of amino acids on cellulose paper. The three-point interaction rule differs from the three-point attachment rule as was pointed out by Davankov [14], who states that the condition for a chiral selector to recognize the enantiomers is that at least three configuration-dependent active points of the selector molecule should interact with three complementary... 

In a nonchiral environment, the enantiomers of a racemate possess the same physical and chemical properties. But in the early 1930s, Easson and Stedman introduced a three-point attachment model that laid the basis for the initial understanding of stereochemical differences in pharmacological activity [13]. The authors described the differences in the bioaffinity of the enantiomers to a common site on an enzyme or receptor surface, with the receptor or enzyme needing to possess three nonequivalent binding sites to discriminate between the enantiomers. The enantiomer that interacts simultaneously with all three sites is called the eutomer (active enantiomer), whereas the other, which binds to fewer than three sites at the same time, is called the distomer (inactive enantiomer) [14]. 

Several additional features of the model are noteworthy. First, it is possible to build it without straining chemical bonds or causing unfavorable steric interactions. The polyamine chain is sufficiently long to reach around a cluster, but it is not so long or so bulky as to cause excessive crowding near the surface of the cluster. The spaces at this surface between the polyamine chains (Fig. 11) are likely binding sites for small apolar molecules, since such molecules can be bound at the interface or partially penetrate into the domain of the hydrocarbon sphere in response to favorable apolar interactions. In the model shown in Fig. 11, three bound p-nitrophenyl caproate molecules have also been included to illustrate possible modes of binding. An arrow points to one of these small molecules. 

Figure 5 Four-point location model. If the target/binding site(s) protrude from a surface or are in a cleft in the macromolecular structure, then either enantiomer may bind at three sites (e.g., B—B, C—C and D—O ), and the bonding interaction is determined by the approach direction. Alternatively a fourth interaction/location...

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