13.4 Enzyme Inhibitors

Enzyme inhibitors are drugs which inhibit the catalytic activity of enzyme. They can be classified as competitive and noncompetitive inhibitors. Competitive inhibitors compete with the substrate for the active site. The greater the concentration of the inhibitor, there is a less probability for the substrate to enter the active site (Figure 5). On the other hand, the greater the concentration of the natural substrate, the less efficient is the inhibition.

Figure 5. Competitive Inhibition

Noncompetitive inhibitors do not compete with the substrate to enter the active site. Instead, they bind at different region of the enzyme and produces an induced fit, which changes the shape of the enzyme such as the active site no longer available to the substrate (Figure 6). Increasing the concentration of the substrate will have no effect on the level of inhibition.

Figure 6. Noncompetitive Inhibition

The binding site of the noncompetitive inhibitors is known as allosteric site. It is often present in the enzyme at the start of the biosynthesis. The allosteric site binds the final product of the biosynthesis and provides a feedback control for the biosynthesis pathway. When the concentration of the biosynthesis product is high, the allosteric site is occupied, the activity of the enzyme is off. The final biosynthetic product is thus used as a lead compound for the design of inhibitors that will bind to the allosteric site (Figure 7).

Figure 7. Allosteric Inhibition

The inhibitors can be reversible or nonreversible. In case of reversible inhibitor, the inhibitor binds with the enzyme through intermolecular interactions such as H-bond, ionic bonding and van der Waals interactions. There will be equilibrium between the enzyme-inhibitor complex and free enzyme and unbound inhibitor. The position of the equilibrium will depend on the strength of the intermolecular interactions between the enzyme and inhibitor. On the other hand, in case of non-reversible inhibitors, the inhibitor may react with enzyme generating a covalent bond. Such bonds are strong and the enzyme remains permanently blocked making the inhibition irreversible (Figure 8).

Figure 8. Irreverisble Inhibition

13.5 Enzyme Selectivity

The inhibitor should be selective for the target enzyme in order to avoid the side effects. There are instances where a particular enzyme may exist in different forms having different amino acid composition, but identical catalytic reaction. These enzymes are called isozymes. If the variation is in the binding site, it is possible to design drugs that will be the isozyme selective.