Apolar binding

Synthetic heterocyclic and modified amino acid derivatives have been grouped in a class of thrombin inhibitors called peptidomimetics. An example of such a compound is argatroban, with a molecular mass of 532 Da. It blocks thrombin s active catalytic site by binding to the adjacent apolar binding site. This selective reversible inhibitor of thrombin has a K of 19 nM and blocks thrombin s role in coagulation and fibrinolysis (62). 

Apolar binding of substrates has been demonstrated with polymers of vinylimidazole. Overberger etal. (77) studied the hydrolysis ofp-nitrophenyl acetate and p-nitrophenylheptanoate by poly[4(5)-vinylimidazole] in ethanol water mixtures. 

As one might expect the rate of p-nitrophenyl heptanoate hydrolysis increased at low ethanol concentrations as a result of apolar binding. The rate of p-nitrophenyl acetate hydrolysis also increased markedly at low ethanol concentration. This finding was explained by a conformational effect on the polymer, that is, lower ethanol concentration brings about a shrinkage of the polymer, which increases concerted interactions of the imidazole residues. The hydrolysis of 3-nitro-4-dodecanoyloxybenzoate was found to be 1700 times faster in the presence of poly[4(5)-vinylimidazole] compared to free imidazole (77). A double-displacement mechanism was demonstrated for this system (75). 

As was mentioned earlier, polyethylenimine has many amine nitrogens in it, and these have the potential to act as nucleophiles (e.g., in an aminolysis reaction). In addition, they are locally concentrated (Figs. 2 and 3). Furthermore, polymers with attached aliphatic acyl groups provide apolar binding sites in proximity to amine residues of the polymer. One might expect, therefore, to find progressively enhanced rates of... 

These characteristics presumably would also be imparted to the apolar binding groups and nucleophilic catalytic moieties covalendy bonded to the polymer. A structure with such features has the potential of being an effective catalyst in a variety of reactions with a range of substrates of widely differing structure and chemical nature. 

Collectively, the direct thrombin inhibitors are prototypically represented by hirudin, the antithrombotic molecule found in the saliva of the medicinal leech (Hirudo medicinalis), This protein is a 65 amino acid molecule that forms a highly stable but noncovalent complex with thrombin (7). With two domains, the NH2-terminal core domain and the COOH-terminal tail, the hirudin molecule inhibits the catalytic site and the anion-binding exosite in a two-step process. The first step is an ionic interaction that leads to a rearrangement of the thrombin-hirudin complex to form a tighter bond that is stoi-chiometrically I I and irreversible. The apolar-binding site may also be involved in hirudin binding. This complex and... 

To help characterize the interactions of some drugs and metabolites with HSA and their competition for its limited number of binding sites, we and others have studied the influence of those substrates on its acetylation by p-nitrophenyl acetate (29,30,31,32,33). This reaction is very fast and results in the irreversible acetylation of a particular tyrosine residue (i.e. 411) which is located in a major apolar binding site of that protein (34). Because this reaction is so fast under most conditions, competing reactions are not significant and formation of p-nitrophenolate is a convenient reflection of the reaction rate (35). 

Berliner L J, Shen Y Y L (1977). Physical evidence for an apolar binding site near the catalytic centre of human a-thrombin. Biochem. 16 4622-4626. 

Figure 4.10. Schematic representation of the co-operativity displayed by binding sites in the formation of organic host-guest complexes. S=hinge, M=metal ion, A=apolar binding site, B=polar binding site, L=lipophilic guest molecule. Reproduced from [182].

Apolar binding plays a key role in the complexation by cyclophanes and will be discussed in some detail before specific classes of receptors are reviewed. Apolar com-... 

Smithrud, D.B. Diederich. F. Strength of molecular complexation of apolar solutes in water and in organic solvents is predictable by linear free energy relationships A general model for solvation effects on apolar binding. J. Am. Chem. Soc. 1990. 772. 339-343. 

These results lead to fundamental questions about the nature of the intermolecular forces responsible for the complexation of the ferrocene guests. As stated before, the rather large binding constant measured between 8 (before oxidation) and host 9 " means that coulombic attraction is responsible only for a relatively small fraction of the stability of the complexes between the calixarene and the cationic guests and 2. We have postulated that these complexation phenomena constitute another example of apolar binding as defined by Diederich[19]. We have recently started calorimetric studies to measure the enthalpic and entropic changes associated with these complexation process. 

M. Komiyama and M. L. Bender (1978), Importance of apolar binding in complex formation of cyclodextrins with adamantanecarboxylate. J. Amer. Chem. Soc. 100, 2259-2260. 

Figure 1 3-D-glucopyranose (21) interpreted as polar and apolar binding regions.

Many enzymes contain deeply buried apolar binding sites within their globular structures. We were interested in using dendritically shielded cyclophanes to mimic such behaviour and this led to the synthesis of a new class of molecules the dendrophanes dendniic cyc ophanes).[ 6] The synthesis of dendrophanes such as 2 (Fig. 2) was... 

Smithrud, D. B. and Diederich, F. (1990) Strength of Molecular Complexation of Apolar Solutes in Water and in Organic Solvents Is Predictable by Linear Free Energy Relationships A General Model for Solvation Effects on Apolar Binding , J. Am. Chem. Soc. 112, 339-343. 

Key words Inclusion complexation, sulfonated calixarenes, redox-active guests, voltammetry, apolar binding. 

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