Chapter five discusses various aspects of receptors as drug targets, such as classification, ligands, and the occupancy theory.

Receptor types

Major receptor superfamilies are introduced:

  • Ligand-gated ion channels
  • G-protein coupled receptors
  • Tyrosine kinase-linked receptors: ligand binding causes receptors dimer
  • Nuclear receptors: not membrane bound and located in nucleus

Ligands

Four types of ligands:

  • Full agonists, which arouse full response of the receptor. Different full agonists can be compared by \(\textrm{log}EC_{50}\).
  • Partial agonists, which arouse only partial response of the receptor. Partial agonists tend to bind to the same position as the full aognists; therefore they often compete with each other. Partial agonists may even suppress the response to full agonists.
  • Antagonists, the efficacy of which can be compared by \(\textrm{log}IC_{50}\).
  • Inverse agonists, which inhibits the constituent activity of the receptor. Cannabinoid receptors are examples of constitutively active receptors.

Two types of antagonist, competitive and noncompetitive, are distinguished. The first type binds to the same site as the agonist, while the second type binds to an allosteric site.

Occupancy theory

Clark’s occupancy theory is introduced, in the center of which lies \(\textrm{Binding}=\textrm{Response}\).

Clark’s equation: \(\frac{E}{E_{max}} = \frac{[L]}{K_D+[L]}\) , where \(K_D = \frac{[R][L]}{[R-L]}\).

At \(EC_{50}\), \([R-L]=[R]\), and therefore \(K_D=[L]=EC_{50}\).

Unfortunately, Clark’s occupancy theory cannot explain all receptors. Exceptions include:

  • Constituent activity
  • Spare receptors
  • Desensitization due to feedback downregulation of the receptor

Alternative theories include the residence time: longer residence time equals greater effect. \(\tau = 1/k_{\textrm{off}}\): the larger the value is, the greater the effect will be. An example is lapatinib, which has though lower \(K_i\) but much longer \(\tau\).

Efficacy and potency

Efficacy and potency are two similar terms with distinct meanings in medical chemistry.

In the context of occupancy theory, efficacy is related to the ability of a molecule to impact a biological pathway while potency refers to the concentration at which the impact occurs. Efficacy is related to \(E_{max}\). \(K_D\) is related to a molecule’s potency.

From a drug-discovery viewpoint, a promising molecule should be both potent and efficacious. In other words, a promising molecule should have as low a value as possible for \(K_D\), meaning the molecule causes its response at very low concentrations. Such a molecule will be potent. A promising molecule should also show efficacy with a high value for \(E_{max}\), signifying that it can elicit a nearly maximum response from a receptor.

Terms

  • \(EC_{50}\) applies to agonists and partial agonists (E stands for effect)
  • \(IC_{50}\) applies to antagonists and inverse agonists (I stands for inhibition)
  • Recall the Cheng-Prussoff equation, \(IC_{50}\) values are usually not comparable between each other, however \(K_i\) is. The conversion is given by \(K_i = \frac{IC_{50}}{1+\frac{[L]}{K_D}}\).

Epilogue

With the end of chapter five, the first part of the course (module 1 and 2) is finished. My impression is that the first part introduces mostly basic concepts in drug discovery,and mostly basic concepts in biochemistry that are relevant for drug discovery.