03.01.2 Drug Binding Sites

Enzymes have binding sites that are usually intended for substrates of that enzyme. The substrate binds to the enzyme, the enzymatic reaction takes place, and a product is produced (Figure 3.2). Drugs can also bind to these sites to have an effect (Figure 3.2). Mostly drugs bind to enzymes to inhibit their actions. Thus, the substrate cannot be turned into the product. This may give a change in a biochemical process for a beneficial effect.

Figure 3.2 Drug and binding site on enzyme (Copyright QUT, Sheila Doggrell)

Ion channels are pores in membrane that open and close to control the movement of ions, such as Na⁺, Ca²⁺, and K⁺, in and out of cells. The movement of ions in and out of cells controls many physiological processes, and is regulated by binding sites. Drugs can bind to these sites to enhance or inhibit the ionic movements (Figure 3.3).

Figure 3.3 Drug and binding site on ion channel (Copyright QUT, Sheila Doggrell)

Carriers can be divided into transporters and pumps. Both of these carry endogenous substances across membranes. Carriers have binding sites for their particular endogenous substance, and drugs may bind to this site, typically to inhibit the carrier (Figure 3.4). For instance, if the activity of a carrier is enhanced in a pathological state, a drug can be used to inhibit the carrier to restore normal function.

Figure 3.4 Drug and transporter (Copyright QUT, Sheila Doggrell)

Naturally occurring substances, such as neurotransmitters and hormone bind to specific receptive substances, which limits their effects to specific sites. Over the years, specific receptive substance has been shortened to receptor. Drugs can bind to receptors to have an action. The binding can be considered to analogous to a key and lock (Figure 3.5).

Figure 3.5 Neurotransmitter, hormone, keys and receptors (Copyright QUT, Sheila Doggrell)

If the drug mimics the effect of the naturally occurring substance at the receptor, the drug is known as an agonist. The key fits the lock, and opens the door. If the drug prevents the action of the endogenous substance, the drug is known as an antagonist. In this case, the key had fitted into the lock but has not opened the door, but has prevented any other keys getting into the lock.

After a receptor is stimulated by an endogenous substance, some intracellular processes occur that lead to the final action. These intracellular processes are known as cell signaling. Drugs can combine with components of the cell signaling to either enhance or inhibit the cell signaling, and hence the final action. Examples of drugs that use all these different binding sites are discussed in turn.

The final actions of a drug depend on the distribution of the binding sites. Although we give drugs to have a beneficial effect, they may also have detrimental effects. Both pharmacological and toxicological actions of drugs are dependent on the use of binding sites. Some endogenous compounds (some enzymes and some neurotransmitters) are widely distributed and have widespread binding sites. Consequently, a drug that uses such binding sites will have widespread effects, and these could include beneficial and detrimental effects. In contrast, some enzymes and hormones are localised, and have localised binding sites. Drugs that bind to localised sites will have a local effect that is, hopefully, beneficial without any widespread detrimental effects.

Another thing that helps localise the effects of drugs, is that there are subtypes of receptors. For instance, the receptor for noradrenaline and adrenaline in the body was originally known as adrenoreceptors, and has been shortened to adrenoceptors over the years. However, noradrenaline and adrenaline do not have identical effects in the body, some are the same, some are different, and the only way this can be explained is by subtypes of receptors, initially α- and β-adrenoceptors (Figure 3.6).

Figure 3.6 Subtypes of receptors (Copyright QUT, Sheila Doggrell)

Further studies have shown that there are many adrenoceptor subtypes. Drugs that stimulate all the adrenoceptors will have widespread effects. Drugs that select one adrenoceptor will have less widespread effects. Noradrenaline and adrenaline stimulate all adrenoceptors to a certain degree, and have the potential to have widespread actions. In contrast, drugs that select the subtypes, as selective agonists or selective antagonists may have localised actions. Selective means it has a greater effect at one receptor than others, it does not mean the drugs specifically stimulates one receptor.

Although adrenoceptors are widespread, the lung has high amounts of one particular type of adrenoceptor, the b₂-adrenoceptors. Salbutamol is a selective b₂-adrenoceptor agonist, and will have effects predominantly mediated by these receptor, including the b₂-adrenoceptors of the lung. Stimulation of the β₂-adrenoceptors in the lung causes bronchodilation. Thus, salbutamol is used as bronchodilator, which does not have all the other widespread effects observed with noradrenaline and adrenaline.

Another example of this is the heart, which has high amounts of b₁-adrenoceptors, and stimulation of the b₁-adrenoceptors leads to an increase in heart rate and force. Atenolol is a selective antagonist at b₁-adrenoceptor, and acts to decrease heart rate and force, leading to a reduction in blood pressure. Atenolol is used in the treatment of hypertension. The effects of atenolol are predominantly limited to heart, and no widespread, potentially detrimental effects, are observed with atenolol.

Receptors are not the only things that have subtypes. There are subtypes of enzymes, ion channels, and carriers. Drugs that selective one of the subtypes have more localised effects than drugs that do not differentiate between the subtypes.