Three-point binding model

Figure 10.8 Three-point binding model for prediction of NeuA stereoselectivity based on conformational analysis.

From an application-oriented perspective, a three-point binding model has been proposed for the conversion of substrate analogs which, on the basis of conformational analysis, can predict the facial stereoselectivity of C—C bonding [22]. 

Figure 6 Three point binding model for prediction of stereoselectivity in NeuA-catalyzed reactions, based on a conformational analysis of C-3 epimeric aldopyranoses as acceptor substrates [22].

After finalization of this review, an independent mechanistic model for NeuA catalysis has been proposed (Fitz, W, Schwark, J-R, Wong, C-H (1995) J Org Chem 60 3663) which is based on consideration of products derived from additions to aldotetroses rather than our conformational analysis and rationalization of a three-point binding motif for the natural acceptor substrate (Sect. 3.1, Scheme 2). 

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]. 

Figure 8 Model of substrate binding to protein lowing a proper three-point binding interaction (A) and of the enantiomer showing an improper three-point binding interaction (B). [Adapted from Christensen (8).]...

In certain cases, a values of 30 or more have been found, which then correspond to A(AG) values in the range of 2 kcal/mol (8.4 kJ/mol). Generally, such values are obtained owing to very low retention of the first enantiomer eluted. This means that a very enantioselective sorption process is operating in the column, i.e., one of the enantiomers is virtually unbound by the CSP for steric reasons. Such phenomena are not easily explained by the three-point interaction model, but rather indicate the operation of a sort of chiral steric exclusion mechanism, more in line with a steric fit concept involving only one binding interaction. ... 

This three point binding mode implies that the chirality of the helix determines the asymmetric induction of the epoxidation and not the chirality of the or-carbon atoms of the peptide catalyst. " Natural enzymes show related arrangements of three NHs as binding motif for fully or partially negatively charged entities. The oxy-anion hole in serine esterase is known to use a similar H-bonding motif as proposed in this 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... 

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