Lecture 2: Drug-Receptor Interactions

• Affinity


  The strength of the bond between a drug and its receptor
• Specificity


  How selectively a drug acts on a particular target
• Efficacy


  The maximum effect a drug can produce
• Potency


  The dose of a drug required to achieve a desired effect
• Affinity and Specificity


  A drug with high affinity for a receptor is likely to be more specific in its effects
• Efficacy and Potency


  A drug's potency is not just about its affinity but also its efficacy. A highly efficacious drug can be potent, even at low doses
• Drug-receptor interactions

  • Drug binding to receptors is a dynamic process, and the occupancy of a receptor is constantly changing until it reaches equilibrium
  • The strength of noncovalent bonds (essential for reversible interactions) between a drug and a receptor, known as affinity, is measured by the dissociation constant (kd) of the drug-receptor complex. Lower kd= higher affinity and stronger a drug-receptor bond
  • The dynamic nature of drug-receptor interactions is influenced by the association rate constant (kon) and the dissociation rate constant (koff)
• Constitutive activity

  Receptors have intrinsic activity in the absence of a ligand, can alter observed drug effects
• Types of drug effects

  • Agonists (binding to and activating the receptor)
  • Inverse agonists (producing a negative effect on the receptor)
  • Antagonists (preventing endogenous agonists from activating receptors)
• Antagonists

  • Non-competitive antagonists that bind to different regions of the receptor than the endogenous ligand (allosteric binding)
  • Some binding may be distorted due to factors such as albumin concentration
• Constitutive activity

  The inherent, baseline activity of a receptor in the absence of any ligands or drugs binding to it
• Constitutive activity

  • It is the level of activity exhibited by the receptor even without the presence of an agonist or antagonist
  • It can alter the observed drug effects by influencing the baseline level of receptor activation
  • Drugs targeting receptors with constitutive activity need to account for and potentially modulate this baseline activity to achieve the desired therapeutic effects
  • It can impact the interpretation of drug binding and efficacy, as it contributes to the overall baseline level of receptor activation and response
• Drug concentration

  Directly affects receptor occupancy, as the rate of binding is proportional to the product of the concentration of the drug and the receptor
• Types of drug binding

  • Agonists (bind to and activate the receptor, increasing occupancy and leading to a positive effect)
  • Antagonists (prevent endogenous agonists from activating the receptors, reducing receptor occupancy and diminishing the effect of the agonist)
  • Inverse agonists (produce a negative effect when bound to a receptor, reducing receptor occupancy and suppressing constitutive activity)
• Equilibrium dissociation constant (kd)

  Measures the drug concentration required to bind half the receptors, indicating the affinity of the drug for the receptor. Low kd values show high affinity, leading to higher receptor occupancy at lower drug concentrations
• Actions of agonists, antagonists and inverse agonists

  • Agonists (produce a positive effect when bound to a receptor, increasing the effect above basal levels)
  • Competitive antagonists (also increase the effect above basal levels, but more agonist is required to achieve the same effect)
  • Non-competitive antagonists (also increase the effect above basal levels, but the maximum effect is reduced, and more agonist is required for intermediate effect)
  • Inverse agonists (reduce the effect below basal levels but require a higher dose to achieve the same effect)
• Drug combinations can have varying effects, with some combinations increasing the effect above basal levels, while others reduce the effect below basal levels or require higher doses to achieve the same effect