Transition state inhibitors approach

A recent example of the success of the bisubstrate, transition state design approach comes from the work of Pope and coworkers (Pope et al., 1998a-c Brown et al., 2000) on the design of inhibitors of bacterial isoleucyl tRNA synthetase... 

Following this strategy, a straightforward approach was developed to d-arabinose-derived methylenebisphosphonate 76 in which one phosphorus atom belongs to the 1,2-phospholane moiety (Scheme 43) [95], This compound was designed as a possible transition state inhibitor of mycobacterial arabinosyltransferases, known to play a crucial role in the biosynthesis of arabinan part of the mycobacterial cell wall. 

This approach has been mainly applied to peptide-based inhibitors of proteases, where the inhibitory molecule is a peptide with a transition state isostere appended to it, and the cognate substrate is simply a peptide of the same amino acid sequence, but lacking the isostere functionality. Examples where good correlations between the free energy of inhibitor binding and the free energy of kcJKM have been found, include peptide-trifluoromethyl ketone inhibitors of human leukocyte elastase (Stein et al., 1987) and peptide-phosphonamidate inhibitors of the metalloprotease ther-molysin (Bartlett and Marlowe, 1983). 

In addition to these studies, the DHFR catalytic mechanism has been studied using the local density function (LDF) approach.22 A detailed understanding of the catalytic mechanism is often very useful in the design of high affinity enzyme inhibitors since it can shed light on the transition state structure and the key interactions used by the enzyme to stabilize it. 

Concept A new approach to the rational design of enzyme inhibitors has emerged in the last ten to fifteen years that incorporates a substrate (or transition state) analog "core" molecule with additional binding determinants spanning beyond the immediate... 

Because a stable transition state analog can only approximate the actual transition state in terms of bond lengths, angles, partial charges, etc., inhibitors using this approach have usually fallen many orders of magnitude short of their theoretical maxi-... 

Interestingly, although many transition state analogs bind noncovalently to the target enzyme s active site via a one-step kinetic mechanism (Scheme la) and would therefore be expected to exhibit no time-dependent properties of inhibition, inhibitors with Kj values of < 10 10 M (like coformy-cin) usually have a slow onset of inhibition kobserved < 10 2 s 1 (i.e., an approach to equilibrium inhibition of > 1 min).161 This is merely an assay artifact due to... 

From a study of overall rate constant k(T) for a reaction in the bulk and its dependence on concentrations of reactants, catalyst/inhibitor, temperature etc., the kinetics come up with a mechanism by putting together a lot of direct and indirect evidences. The determination of the overall rate constant k(T) using transition state theory was a more sophisticated approach. But the macroscopic theories such as transition state theory in different versions are split to some extent in some cases, e.g. for very fast reactions. The experimental and theoretical studies in reaction dynamics have given the indications under which it becomes less satisfactory and further work in this direction may contribute much more to solve this problem. 

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). 

The strategy of designing saquinavir was based on the transition-state mimetic concept, an approach that has been used successfully in the design of potent inhibitors of renin and other aspartic proteases [10]. From the variety of nonscissile transition-state analogs of a dipeptide, the hydroxyethylamine mimetic was selected because it most readily accommodates the amino acid moiety characteristic of the Phe-Pro and Tyr-Pro cleavage sequence of the... 

Phosphonopeptides containing a transition state analog of the hydrolysis of the amide bond represent another attractive approach for the preparation of proteolitically stable peptides (10,30,31). In addition to increased stability, incorporation of a phosphonate moiety into the peptide sequence provides access to additional binding interactions within the transition-state conformation of the enzyme/substrate complex (13). This peptidomimetic approach is used to design very effective protease inhibitors (31-34). As in the case... 

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