Ground-state analogs, design

In our context, an important class of reversible inhibitors are the transition state analogs [18], which are stable compounds designed to mimic the structure of an intermediate in the path of substrate s transformation by the enzyme. Such analogs are based in Pauling s postulate [19], which states that "an enzyme recognises and binds more tightly to the transition state than to the ground state of the substrate". 

The molar free enthalpy G, in analogy to a mechanical system, is called the chemical potential and is designated with p ( i = G). In a mechanical system, a body moves in the direction of decreasing potential (e.g. an object falls to earth or a ground state) and from this comes the analogy to the chemical potential. 

Due to its diamagnetic ground state, intermediate Q is not readily accessible to study by EPR-related techniques. However, radiolytic reduction of Q has been shown to produce a structurally preserved but paramagnetic Fe Vpe" species, designated Qx [107] (in analogy to intermediate X in ribonucleotide reductase vide infra). Annealing of this intermediate above 200 K produced a structure essentially identical to that of the chemically reduced intermediate at room temperature. 

Since binding interaction between an enzyme and a substrate is more favorable (>10 ) at the transition state than at the ground state, a transition state analog was expected to be a much better inhibitor than a substrate analog. Therefore, design of analogs of transition-state in the enzyme catalytic reaction was another popular field of research on PDHc inhibitors [54]. The normal enzyme-catalyzed pyruvate metabolic process is described in Scheme 1.13 [42]. 

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