Drug classes, targets and receptors

  • Drug classes
  • Drug protein target classes and RICE
  • Four receptor families and how can activation of a receptor lead to a biological effect?

Learn.

There are a number of ways to classify drugs – they can be classed based on their; Molecular structure, mechanism of action, mode of action and their therapeutic effects.

These drugs can then act on protein targets. The types of protein targets can be classified into receptors, ion channels, carrier molecules and enzymes. The acronym rice can helpt to remember thes protein targets.

Binding specificity is the measure of a proteins ability to bind to other ligands- the higher the specificity the fewer number of ligands it can bind to the greater the specificity. Binding selectivity is the measure of a ligand binding more favorably to one receptor to another one. The greater both of these are, the more favorably a drug will, therefore, bind to them. Bonds between drug targets and receptors are often week and reversible – these bonds often start with ionic bonds since they can act over long distances. Once the drug and protein are in close proximity hydrogen bonds and van der waals forces begin to strengthen this bond. A drug’s attraction to a forming a drug-receptor complex is it’s affinity.

Cells communicate through chemical sensors – these sensors are known as receptors which allow for chemical communication. The mediator is what activates the receptors. Orphan receptors are receptors with yet unknown mediators.

Drugs that act on receptors can be agonist , inverse agonist – they mimic the shape of endogenous chemical signals (the mediators). An endogenous chemical signal just means that it is made by the body. As a result the agonist which mimics the mediator can bind to and activate the chemical receptor. An example of this is acetylcholine which is an endogenous neurotransmitter which can be mimicked by acetyl choline. The effect of the agonist can be the opening or closing of an ion channel, inhibition or activation of an enzyme, the modulation of an ion channel or DNA transcription.

An antagonist blocks the endogenous mediator by binding to the receptor site. Hence it inhibits the action of the receptor. Curare is an example of this for the endogenous mediator acetylcholine.

Ion channels allow charged particles to diffuse across a cell membrane. The can be ionotropic receptors – these allow ions such as  Na⁺, K⁺, Ca²⁺, and/or Cl⁻  to pass through when a mediator binds to them, hence they are ligand-gated ion channels. Voltage-gated ion channels (VGICs) open and close in response to a change in membrane potential. For example local anesthetics block nociception (neurotransmission of pain) by binding to voltage-gated channel’s internal pore. Ion channels can be blocked by blockers or they can be opened or closed by modulators.

Transporters allow molecules to move against a concentration gradient – aka carrier molecules. You can have both a false substrate where an alternate molecule is transported across membrane or an inhibitor which prevents the transoportation of a molecule.

Enzymes lower the activation energy required for a reaction to proceed, thereby, increasing the rate of reaction. There are three techniques to target enzymes – enzyme inhibition, false substrate and prodrugs. Inhibition occurs when the an inhibitor binds to the active site of an enzyme, preventing normal function of an enzyme. Acetylsalicylic acid, sold under brand name Aspirin, inhibits the enzyme cyclo-oxygenase. A false-substrate uses a drug which is metabolized by an enzyme to form an abnormal metabolite which can then be harmful to a cell. A prodrug can be administrated to be the precursor of a drug so an enzyme metabolizes – increasing uptake.

Four protein receptor families:

  • Ionotropic receptors

The Nicotinic acetylcholine receptor is an example of this where acetylcholine is the mediator. Ligand-gated ion channels can respond over milliseconds. Example of receptors include nACH and GABAA receptors.

  • G-protein coupled receptor:

These are slow acting synaptic transmission mediators which often take seconds. These have 7 transmembrane proteins studded in the membrane of the cell. On one side of the nucleotide is the guanine coupling domain. Of the 4 main g proteins; Gαq, G αs, G αi, G αo they either link to enzymatic or ion channel pathways.

  • Kinase-linked receptors

Kinase is an enzyme which catalyzes the transfer of phosphate groups from high energy molecules to certain substrates. For kinase-linked receptors a single transmembrane helix goes through the cell membrane with a catalytic domain one one side and a binding domain on the other. These act over minutes e.g growth factors.

  • Nuclear receptors

Nuclear receptors are slow acting on timescale of hours – day/s. Since they regulate gene transcription they are not found on cell membranes.

Memorize.

Master.

Question 1. [3 marks]

Using an example, explain how knowledge of protein receptors can allow for drugs to be designed to mimic an endogenous mediator.

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