Transition-state analogues affinity

Design of extremely high-affinity transition-state analogues,... 

For the tight binding of the transition state the binding surface of the enzyme must be complementary to the structure of the transition state, so that optimal interactions between the enzyme and the transition state are possible. This demand imphes that enzymes display a high affinity to molecules which are chemically similar to the transition state of the reaction. Complexes of such transition state analogues with enzymes are well suited for X-ray structure analysis to elucidate the structural principles of the active site and the catalytic mechanism. 

Lee JE, Singh V, Evans GB, Tyler PC, Furneaux RH, Cornell KA, Riscoe MK, Schramm VL, Howell PL (2005) Structural rationale for the affinity of pico- and femtomolar transition state analogues of Escherichia coli 5 -methylthioadenosine/S-adenosylhomocysteine nucleosidase. J. Biol. Chem. 280 18274-18282... 

Selection by affinity chromatography on a transition-state analogue has also been used to extract active enzymes from a library of phage-displayed GST Al-1 mutants. Four residues in the electrophilic substrate binding site were randomly mu-... 

Selection with transition-state analogues has also been used to extract catalytic antibodies from libraries of phage-antibodies. McCafFerty et al. [52] have shown that antibodies with nanomolar affinities for a phosphonate transition-state analogue could easily be extracted from a library derived from immunized mice. 

In general, the term transition-state analogue is used broadly in this review to cover inhibitors for which the term defines the rationale behind their design. The detailed kinetic analyses and comparison of affinity to analogous substrates, which need to be done to prove a compound a transition-state analogue, have not always been done. In many cases these compounds could be more accurately described as mimics of high-energy intermediates in the enzymatic pathway. 

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... 

Compound 13 represent a transition state analogue of the A-acetylneuraminyl cation during the enzymatic reaction (Scheme 3). According to a postulate by L. Pauling compounds that closely resemble the transition state have higher binding affinity toward the... 

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