Viva C(iv)

This viva is relevant to the objectives of Section C(iv) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "explain receptor activity with regard to... structural relationships for receptors and ligands".

What is a "ligand"?
  • A ligand is a molecule that binds to another (usually larger) molecule.
  • Ligands are usually small molecules; but they range from ions and small peptides to dissolved proteins.
What is a receptor?
  • Receptors are generally large proteins with a complex structure. 
  • A receptor is defined by Goodman And Gilman as: 
  • "the cellular macromolecule or macromolecular complex with which the drug interacts to elicit a cellular or systemic response"
  • This is in contrast to a drug acceptor such as albumin, to which the drug binds with no discernable physiological effect. 
What is described by the term "pharmacophore"?

"A molecular framework that carries (phoros) the essential features responsible for a drug’s (pharmacon) biological activity".

Or, the 1998 IUPAC definition:

"An ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response"

Explain the concept of molecular complementarity
  • The term "molecular complementarity" describes the matching of surface shape and chemical properties between receptors and ligand molecules.
  • It is essential for high-affinity bonds to form.
  • Both the surface structure and the chemical properties of the ligand-binding site must fit the ligand.
  • Some ligands are  "privileged scaffolds", molecular structures which seem to act as ligands for a whole array of receptors (Welsh et al, 2010). (eg. quinoline rings - the reason for why hydroxychloroquine is both an antimalarial agent and an immunosuppressant).
How do receptors and ligands interact? 
  • Van der Waals forces (most important for highly complimentary molecules, for example monoclonal antibodies and their targets)
  • Hydrophobic attraction (eg. sugammadex and rocuronium)
  • Hydrogen bonding (binding of a local anaesthtic to a voltage-gated sodium channel).
  • Electrostatic attraction, eg. acetylcholine and its receptor
  • π–π "stacking" interactions between aromatic rings or π– cation interactions, eg. neurotransmitters such as dopamine
  • Covalent bonds (a "suicide" bond - eg. phenoxybenzamine)
What are the different receptors which act as drug targets? Give some examples.

Another way to word this would be, "what are the different mechanisms by which drugs achieve their therapeutic effects?"  or "what different classes of drug targets are there?"

  • Extracellular
    • Soluble extracellular enzymes (dabigatran, perindopril)
  • Cell surface
    • Cell surface molecules (abciximab)
    • Transmembrane nonenzymes (cytokines, interferon-γ)
    • Transmembrane proteins with active domains eg. receptor kinases (insulin, imatinib)
    • Ligand-gated ion channels (nicotine, suxamethonium)
    • Voltage-gated ion channels (lignocaine, verapamil)
    • G-protein coupled receptors (dobutamine, metoprolol)
  • Intracellular
    • Soluble intracellular enzymes (glyceryl trinitrate, milrinone)
    • Nuclear receptors (corticosteroids, thyroxine)
    • Nucleic acids (doxorubicin, azithromycin)

References