Transition-state analogues concept

The use of the transition-state analogue concept is an effective approach in the design of potent enzyme inhibitors. For the aspartyl proteases, structures that mimic the tetrahedral hydrated amide formed during the peptidic bond hydrolysis led to the preparation of compounds with very high binding affinity to the enzymes. In the... 

As mentioned in the Introduction, various authors have been influenced (directly or indirectly) by the Kurz approach in their discussions of enzyme behaviour (e.g. Wolfenden, 1972 Lienhard, 1973 Jencks, 1975 Schowen, 1978 Fersht, 1985 Kraut, 1988 Wolfenden and Kati, 1991). Also, as noted earlier, the concepts of transition state binding and stabilization were crucial to the development of transition state analogues as enzyme inhibitors and hence as chemotherapeutic agents (Jencks, 1969 Wolfenden, 1972 Wolfenden and Frick, 1987 Wolfenden and Kati, 1991). 

A similar concept was used in the development of artificial chymotrypsin mimics [54]. The esterase-site was modeled by using the phosphonate template 75 as a stable transition state analogue (Scheme 13.19). The catalytic triad of the active site of chymotrypsin - that is, serine, histidine and aspartic acid (carboxy-late anion) - was mimicked by imidazole, phenolic hydroxy and carboxyl groups, respectively. The catalytically active MIP catalyst 76 was prepared using free radical polymerization, in the presence of the phosphonate template 75, methacrylic acid, ethylene glycol dimethacrylate and AIBN. The template removal conditions had a decisive influence on the efficiency of the polymer-mediated catalysis, and best results were obtained with aqueous Na2CC>3. 

The concept of electrostatic catalysis has been applied indirectly by Schramm and coworkers for the design of transition-state analogues in reactions by nucleoside hydrolase (Horenstein et al., 1991 Horenstein and Schramm, 1993) and AMP deaminase (Kline and Schramm, 1994). They stated, in accordance with our previous examples, that the MEP provides novel insight into transition-state structure and the forces associated with substrate binding and release. 

If enzymes bind transition states more tightly than substrates, then they should bind molecules which resemble transition states in shape and/or charge more tightly than they bind substrates or products. The concept of transition state analogue was first applied to glycosyl transfer by Leaback, " who... 

The formation of a spatially and functionally specific cavity has an obvious application in enzyme type catalysis [112]. Furthermore, in the light of interest in catalytic antibodies [113], the analogy between antibody and MIP suggests the concept of catalytic plastibodies . Robinson and Mosbach [114] demonstrated the potential for catalytic activity by imprinting a transition state analogue (p-nitrophenylmethyl-phosphonate) of the hydrolysis of p-ni-trophenylacetate (Figure 6.29)... 

Later, various aspects of the catalytic actions of specifically formed adsorbents as catalysts were discussed by Jencks, who theorized that antibodies prepared in the presence of stable analogues that mimic transition states may be able to catalyze the corresponding reactions. Recently Lemer and Mosbach used transition states analogues to imprint the formation of antibodies that were able to function as catalysts for reactions from which the transition-state analogues were prepared. Confirmation of these concepts was obtained fi om studies of the Claisen rearrangement of (-)-chorismate to form prephenate... 

Development of catalytic antibodies or abzymes is another fascinating approach to artificial enzymes. The concept of catalytic antibodies is that if a putative transition state analogue of a reaction for which a selective and efficient catalyst is desired is used to elicit antibodies. 

It has been found that various sugar oxazoline derivatives serve as monomers for enzymatic catalysis to produce natural and unnatural mucopolysaccharides, in which the monomers were designed and synthesized on the basis of the transition-state analogue substrate (TSAS) concept vide infra).All the sugar oxazoline monomers are of AB-type structure mentioned in Section 4.15.3.2. 

For systems with a continuous spectrum, the concept of chaos is not defined in classical mechanics,66 since at least some trajectories will escape from the interaction region, as t -> oo. One could introduce a definition based on the notion of cantori, which act as barriers in phase space67 and which can serve68 to provide an analogue of a transition-state configuration for systems whose time evolution is constrained. Our own preferred interpretation is based on the discussion of Section III E. The fluctuations in rates are with respect to the zero-time limit of the dynamics. When v = 1, it is not necessary to propagate the system for a finite time in order to be able to predict the rates. The variation in rates are just the inherent fluctuations about the conventional, statistical specific features that... 

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