Intro to Molecular Pharmacology

• Many drugs share a ring structure as a common theme
• Why do many drugs have a ring structure?

  Provides rigidity and a restricted conformation which is important for interactions with drug targets
• Humans are living longer due to the development of drugs, meaning that more deaths are attributed to cancer and cardiovascular disease
• Less people died during the covid pandemic than they did from the influenza pandemic due to drugs and vaccines
• Proteins are the main targets for drugs
• Cell surface targets

  • Transporters
  • Receptors
  • Ion channels
• Intracellular targets

  • Enzymes
  • Nuclear receptors
  • Protein synthesis
• Actions of drugs on receptors

  agonist, antagonist, modulators
• drug inhibitors prevent the enzyme from doing the normal substrate reaction
• False substrates are metabolised by the enzyme to produce a toxic compound or occupy the enzyme
• Drug actions of transporters

  blockers and false substrates
• drug actions of enzymes

  inhibitors and false substrates
• False substrates are transported in place of the endogenous substance
• In the early days, most drugs were discovered by serendipity
• Biological/chemical wisdom can inform what constitutes an effective drug
• Genomics can inform which genes encode for the gene to target
• Where do lead compounds come from?

  • Natural products
  • Random screening of compounds
  • Combinatorial chemistry
  • Structure-based drug design
• Random screening of compounds

  • Generate a variety of molecules and test each to find which is most effective
• • Combinatorial chemistry
  • Start with a simple molecule and add structures until it is effective
• Structure-based drug design

  • Design a drug with a structure that fits in a particular target
• What Makes a Good Drug?

  • Effective
  • Non-toxic
  • Minimal side effects
  • Bioavailability
  • Mechanism of action
  • Inexpensive to manufacture
  • Acceptable route of administration
• Pharmacodynamics

  • The effect of a drug on the body
• Pharmacokinetics

  • The effects of the body on the drug
• Bioavailability is affected by:

  • Different pH environments of the body
  • Diffusion through cell membranes
  • Blood-brain barrier
  • Metabolism
  • Off-target binding
• pKa is a measurement of acidic strength
• pKa allows us to predict what form a drug will be in for certain environments
• Ionic forms of drugs penetrate membranes slowly, but allow for strong ionic bond interactions with targets
• The equilibrium will change when the drug enters a new compartment that is a different pH
• Only the neutral form of a drug will pass through the membrane
• A drug with pKa close to neutral pH will easily cross the membrane
• Optical Isomers have the same physiochemical properties
• optical isomers have the same chemical groups but they are in different 3D positions
• Usually, optical isomers do not have the same activity
• optically pure drugs (the more active isomer) are preferred over racemic mixtures