Hydrophobic interactions receptor binding

The tweezer-type receptor 43 that was developed by Kilbum and coworkers contains a disnbstitnted guanidinium group in the middle of the chain which was expected to bind to the terminal carboxylate gronp of peptidic guests (Scheme 22). The two peptide arms that are arranged in a parallel fashion serve to induce substrate selectivity. To test this idea, 43 was incubated in aqueous sodium borate buffer (pH 9.2, 16.7% DMSO) with a 1000-member library of tripeptides attached to a TentaGel resin via the amino terminus. Mainly hydrophobic amino acid residues were incorporated into these tripeptides to ensure that receptor substrate interactions are largely due to hydrophobic interactions. Receptor 43 was found to bind to about 3% of the library members and showed 95% selectivity for Val at the carboxylate terminus of the tripeptides and 40% selectivity for Glu(OfBu) at the amino terminus. A stability constant of 4 x lO M- was determined for the complex between 43 and Z-Glu(OrBu)-Ser(OfBu)-Val-0 in 16.7% DMSO/water (1 mM sodium borate buffer, pH 9.2) by means of isothermal titration microcalorimetry. 

These results suggests that stronger hydrophobic interactions between the aromatic end-group of 27 and the P-CD cavity are favoring the 1 1 inclusion complex with the central double bond just under the reactive 0 = Ru = 0 center. In contrast, 1, 25 and 26 slide within the CD cavity exposing three double bonds rather than one to the reactive Ru = 0. Determination of the binding constant of 27 to the receptor 10 supports this interpretation, i.e., (27-10) — 5.0 x... 

Thus, non-covalent hydrophobic interactions, hydrogen bonds, and electrostatic bonds all contribute to the overall shape of a protein (Figure 13.3). As we shall see (Section 13.3.2), many pertinent properties of a protein are then provided by the appropriate combination of the remaining amino acid side-chains that reside on the surface, allowing specific binding to various molecules. This is the essence of enzymic activity and drug-receptor interactions. 

The results of the receptor binding assay performed using this compound, IA, are shown in Table 4 where it is clear that affinity to the human B2 receptor is improved with respect to compound I. This data is supportive of the notion that the C-terminal residue(s) in this new series of bradykinin antagonist compounds interact with a hydrophobic environment, perhaps within the transmembrane domain of the receptor as previously suggested. 

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