Medicinal Chemistry

anhydrase, which regulates proton equilibria in the kidney. Another ubiquitous enzyme
is adenylate cyclase; many drug receptors are coupled to it directly and exert their activity
by regulating cAMP production.
Enzymology is a large and complex subdivision of biochemistry, and no attempt will
be made to cover it in this book. The reader who requires a review of enzyme kinetics
and mechanisms is referred to the many currently available and excellent textbooks of
biochemistry.

8.2.1 Mechanisms of Enzyme Inhibition

Enzyme inhibitors inhibit the action of enzymes either reversibly or irreversibly. Since
enzymes are such pervasive, powerful biological catalysts, inhibitors can act as potent
drugs. Broadly categorized, enzyme inhibitors may be either irreversible or reversible.
Irreversible inhibitors combine or destroy a functional group on the enzyme so that
it is no longer active. They often act by covalently modifying the enzyme. Thus a new
enzyme needs to be synthesized. Examples of irreversible inhibitors include acetylsal-
icyclic acid, which irreversibly inhibits cyclooxygenase in prostaglandin synthesis.
Organophosphates (e.g., malathion, 8.10) irreversibly inhibit acetylcholinesterase.
Suicide inhibitors (mechanism-based inactivators) are a special class of irreversible
inhibitors. They are relatively unreactive until they bind to the active site of the enzyme,
and then they inactivate the enzyme.

There are four types of reversible enzyme inhibitors:

1. Competitive inhibitors.These compete with the normal substrate for the enzyme’s
   binding site. This does not affect the maximum rate of the reaction but does mean
   that more substrate has to be supplied. For example, to treat cases of methanol inges-
   tion, ethanol is used to compete with methanol. Most drugs that act as reversible
   inhibitors are competitive inhibitors.


2. Non-competitive inhibitors.These inhibitors bind to the enzyme or the enzyme–
   substrate complex at a site other than the active site. This results in a decrease in the
   maximum rate of reaction, but the substrate can still bind to the enzyme. An analogous
   concept is that of allosteric inhibition. The site of binding of an allosteric inhibitor
   is distinct from the substrate binding site. In this case, the inhibitor is not a steric
   analog of the substrate and instead binds to the allosteric site(the phenomenon was
   termed thus by Monod and Jacob).

484 MEDICINAL CHEMISTRY