Concept 01 / 05Chemistry in Everyday Life
Drugs and Their Molecular Targets: Enzymes and Receptors
What drugs and medicines are, the four bases of classifying drugs, drug-target interaction, enzymes as targets (catalytic action, competitive, allosteric and irreversible inhibitors) and receptors as targets (chemical messengers, agonists and antagonists).
Drugs are chemicals of low molecular mass (about 100 to 500 u) that interact with macromolecular targets in the body and produce a biological response. When the response is therapeutic and useful, the drugs are called medicines, used in the diagnosis, prevention and treatment of disease. The use of chemicals for therapy is chemotherapy. Almost every drug is harmful at a high enough dose.
Classification of drugs.
By pharmacological effect: for example analgesics (pain relief) or antiseptics (kill or arrest microbes). This is useful to doctors.
By drug action on a particular biochemical process: for example antihistamines, which inhibit the action of histamine.
By chemical structure: drugs with a common structural feature often act similarly, for example sulfonamides.
By molecular target: drugs that act on the same target, useful to medicinal chemists.
Drug-target interaction. Targets are proteins (enzymes and receptors), carbohydrates, lipids and nucleic acids.
Enzymes as targets. An enzyme holds its substrate in the active site by ionic bonding, hydrogen bonding, van der Waals forces or dipole-dipole attraction, and provides functional groups that attack the substrate. Drugs that inhibit enzymes (see figure):
Competitive inhibitors compete with the substrate for the active site.
Allosteric (non-competitive) inhibitors bind a different site, the allosteric site, changing the shape of the active site so the substrate cannot bind.
If an inhibitor forms a strong covalent bond with the enzyme, the inhibition is irreversible; the body must synthesise new enzyme.
Receptors as targets. Receptors are proteins embedded in cell membranes, with the active site facing outwards. Chemical messengers such as neurotransmitters and hormones bind to the receptor, which changes shape and transfers the message into the cell without the messenger entering it; the messenger then leaves and the receptor returns to its original form. Drugs that bind receptors act in one of two ways:
Antagonists bind the receptor site and block the natural messenger; they are useful when the message must be stopped.
Agonists mimic the natural messenger and switch on the receptor; they are useful when the natural messenger is lacking.
Receptors are highly selective, which is why each messenger or drug acts on particular tissues.
Key Takeaways:
- A drug becomes a medicine when its effect is therapeutic.
- Four bases of classification: pharmacological effect, drug action, chemical structure, molecular target.
- Competitive inhibitors block the active site; allosteric inhibitors bind elsewhere and distort it.
- Agonists mimic the messenger; antagonists block it.
- Pitfall: a drug classed by molecular target is grouped by what it binds, not by what disease it treats.
Brain-Teaser 1: A patient's nerve cells release too little of a neurotransmitter. Should the drug be an agonist or an antagonist of its receptor? What if the neurotransmitter is overproduced?
Solution: Too little messenger: an agonist, which mimics it and activates the receptor. Too much messenger: an antagonist, which occupies the receptor and blocks the excess messenger from delivering its signal.
Brain-Teaser 2: Adding a large excess of substrate restores the rate of an inhibited enzyme reaction in one case but not in another. Identify the type of inhibitor in each case.
Solution: If excess substrate restores the rate, the inhibitor is competitive: substrate and inhibitor compete for the same active site, so a high substrate concentration wins. If it does not, the inhibitor is allosteric (or irreversible): it acts at a different site or is covalently bound, so substrate cannot displace it.
Brain-Teaser 3: Why are irreversible enzyme inhibitors generally more dangerous than reversible ones?
Solution: An irreversible inhibitor forms a covalent bond with the enzyme and permanently deactivates it. Activity returns only when the body synthesises new enzyme molecules, which takes time, so the effect persists even after the drug is no longer present (nerve agents that block acetylcholinesterase act this way).
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