Enzyme inhibitors, structure-function

Many examples exist of potent enzyme inhibitors that function as transition state mimics (see Chapter 7 Schramm, 1998, and Wolfenden, 1999, for some examples). An understanding of the transition state structure is thus of great valuable for inhibitor design. As described in Chapter 1, the transition state is not the only inter-... 

MMP inhibitor development constitutes an important branch of research in both academic and industrial settings and advances our knowledge on the structure-function relationship of these enzymes. Targeting... 

It is worth noting here that inhibitors that interact with enzyme active site functionalities in ways that mimic the structure of covalent intermediates of catalysis can bind with very high affinity. This was seen in Chapter 1 with the example of statine-and hydroxyethylene-based inhibitors of aspartic proteases other examples of this inhibitor design strategy will be seen in subsequent chapters of this text. 

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. 

Targeted libraries have been most effective when based upon the display of diverse functionality about a minimal mechanism-based pharmacophore targeting an enzyme family. Early successes with this approach were first achieved with proteases.1221 Our own efforts to design libraries which target enzyme families require that the minimal pharmacophore serves as the site for attachment to solid support.1231 The pharmacophore is the only invariant part of the inhibitor structure, which... 

The optimum structure for the first transition state placed the Asp" residue (i.e. our formic acid) reasonably close to the position in which it is found in the enzyme-inhibitor crystal structure [64], However, this functional group is not at all rigid in our model problem. It... 

To close on a more positive note, we observe that the computed geometry of the enzyme-dienolate complex in the vicinity of the 3-carbonyl is insensitive to the assumed dielectric constant and is in close agreement with X-ray structures of enzyme-inhibitor complexes (see Table 4.11 and Fig. 4.15). It is really quite remarkable that 4 billion years of random walk by mother nature and a few hours of optimization with a quantum chemistry program such as Gaussian (starting with the correct functional groups) lead to the same structure for the active... 

In a very broad overview of the structural categories one can state several statistical correlations with type of function. Hemes are almost always bound by helices, but never in parallel a//3 structures. Relatively complex enzymatic functions, especially those involving allosteric control, are occasionally antiparallel /3 but most often parallel a//3. Binding and receptor proteins are most often antiparallel /3, while the proteins that bind in those receptor sites (i.e., hormones, toxins, and enzyme inhibitors) are most apt to be small disulfide-rich structures. However, there are exceptions to all of the above generalizations (such as cytochrome cs as a nonhelical heme protein or citrate synthase as a helical enzyme), and when one focuses on the really significant level of detail within the active site then the correlation with overall tertiary structure disappears altogether. For almost all of the dozen identifiable groups of functionally similar proteins that are represented by at least two known protein structures, there are at least... 

Finally, there is a class of molecules—some large and many small— termed enzyme inhibitors. These molecules bind to enzymes, generally quite specifically, and prevent them from carrying out their catalytic function. These are keys that fit the lock but do not open it. This is another example of molecular recognition. In the simplest cases, the inhibitor of an enzyme is structurally related to the normal physiological substrate for the enzyme. The inhibitor looks enough like the normal substrate to bind to the enzyme at the site where the substrate normally binds but is sufficiently different so that no reaction subsequently occurs. The key fits in the lock but cannot open it. It follows that the enzyme is captured in the form of an enzyme-inhibitor complex, E 1, where 1 denotes the inhibitor. The point is that E 1 cannot make products. The enzyme has been rendered nonfunctional as long as 1 is bound to it. 

Another retrospective analysis of already known H DAC inhibitors was carried out by You et al. [68]. They generated a 3D chemical-feature-based pharmacophore model and compared the ligand-based model with the structural-functional requirements for the binding of the HDAC inhibitors. Using this model, the interactions between the benzamide MS-275 and HDAC were explored. The result showed that the type and spatial location of chemical features encoded in the pharmacophore are in full agreement with the enzyme-inhibitor interaction pattern identified from molecular docking. However, also in this study no experimental validation of the modeling results was provided. 

Suicide Enzyme Inhibitors. Snicide substrates are irreversible enzyme inhibitors that bind covalently. The reactive anchoring group is catalytically activated by the enzyme itself through the enzyme-inhibitor complex. The enzyme thus produces its own inhibitor from an originally inactive compound, and is perceived to commit suicide. To design a substrate, the catalytic mechanism of the enzyme as well as the nature of the functional gronps at the enzyme active site must be known. Conversely, successful inhibition provides valuable information about the structure and mechanism of an enzyme. Componnds that form carbanions are especially usefnl in this regard. Pyridoxal phosphate-dependent enzymes form such carbanions readily becanse... 

---