Biochemical Interactions

• When researchers first began to isolate active ingredients from plants, it was not known how they have their effects on the body
• Gradually chemical structure started to be linked to biological activity
• Compounds with a quaternary amine


  • Often found to either relax or contract muscle
• Receptor


  A site where a drug binds and then the receptor brings about a physical response
• Ligand


  The drug that binds at the receptor
• Agonist


  A ligand that binds at the receptor and produces the expected response
• Cholinergic receptors


  The receptor family where muscle relaxants act
• Acetylcholine


  The naturally occurring agonist at cholinergic receptors
• Drug-receptor complex formation


  Drug fits into the receptor, resulting in a physiological response
• Antagonist


  A drug that binds to the receptor but does not give rise to a physical response, blocking the receptor

  
• Drugs can also bind to enzymes, which are made up of proteins</b>
• Functional groups in proteins


  • Acidic
  • Basic
  • Neutral
  • Polar
  • Non-polar
  • Ionised
• Drugs form interactions with the functional groups lining the active site of the receptor or enzyme
• Drugs binding at the same site but in a different way can give rise to different effects (e.g. agonists and antagonists)
• Knowledge of these interactions allows us to work out how a drug binds, design new drugs and predict how they will bind
• Van der Waals bonds


  Weak bonds that exist between all atoms due to the constant movement of electron clouds
• Van der Waals bonds

  • Larger surface area and more electrons in molecules leads to stronger interactions
  • Only occur between molecules very close together (0.4-0.6 nm)
• As distance between molecules increases


  Van der Waals force decreases (force α 1/d^6)
• Dipole-dipole interactions


  Electrostatic interactions between permanent dipoles in molecules
• Hydrogen bonds


  Special type of dipole interaction formed between functional groups containing N, O or S and H
• Hydrogen bonds


  • Stronger than usual dipole-dipole interactions
  • Directional
• Hydrogen bonds play a significant role in drug-target interactions, protein structure, and DNA structure
• Ion-dipole bonds


  Bonds formed between ionised functional groups in drugs and permanent dipoles
• Ionic bonds


  Strong bonds formed between species with opposite charges
• Drugs are often ionised and receptor active sites contain charged groups, allowing for ionic bonding
• Covalent bonds


  The strongest type of bond, some drugs can form covalent bonds with targets
• Covalent bonds are strong and irreversible, permanently inhibiting enzymes
• Some anti-cancer drugs alkylate DNA via covalent bonding, leading to cell death
• Hydrophobic attraction


  The tendency for non-polar molecules to cluster together in water to minimise disruption of water's hydrogen bonding network
• When a drug and binding site are surrounded by water


  Hydrophobic attraction can bring them together, displacing structured water and allowing more specific interactions

  
• Most drugs/biomolecules have both polar and non-polar groups, allowing them to dissolve in water and associate with hydrophobic molecules
• Optical isomerism


  Molecules with stereocentres that exist as mirror image pairs (enantiomers)
• Optical isomers


  • Usually only one enantiomer has the desired biological activity
  • The other enantiomer may cause side effects or be metabolised to a toxic product

  
• Geometrical isomerism


  Isomerism that occurs when there is no free rotation about a bond, e.g. double bonds
• Conformational isomerism


  Molecules can adopt preferred shapes although they can exist in other conformations
• If the drug has a preferred conformation that fits the active site, it will usually bind more easily