Shapes and Properties of Drugs

• the Nicotinic acetylcholine receptor is a Ligand-gated ion channel
• How many subunits come together to form the nAChR ion channel?

  five
• There are many subtypes of the alpha and beta subunits of nAChRs
• the Muscarinic acetylcholine receptor is a G protein coupled receptor
• the Muscarinic acetylcholine receptor consists of a 7 transmembrane domain protein coupled to a trimeric G-protein
• There are five subtypes of muscarinic acetylcholine receptors, each of which has a different coupling capacity with G proteins
• Specificity of drug interactions is often mediated by amino acid side chains
• Side chains can be grouped according to chemical types:

  • Aliphatic
  • Aromatic
  • Polar and uncharged
  • Positively charged
  • Negatively charged
• Different side chains can form different types of bonds with drugs
• Covalent bonds are the strongest, followed by ionic bonds
• Hydrogen, dipole-dipole and hydrophobic bonds are weak
• Covalent Bonds are not very common in drug-receptor interactions
• Example of covalent bonds in drug action

  aspirin binds to cyclooxygenases: The acetyl group of aspirin is transferred to a serine residue in the active site of the enzyme, causing irreversible inactivation of the enzyme
• Ionic Bonds are formed between charged groups of a ligand/drug and arginine, lysine, histidine, aspartate, or glutamate residues in protein targets
• Ion-Dipole and Dipole-Dipole Bonds

  A lone pair of electrons on a target residue (e.g. serine) is attracted to a positive charge on the drug/ligand
• Hydrogen Bonds are very common but weak
• Hydrogen bonds are directional: they only form in a straight line
• the directionality of hydrogen bonds helps to orientate the molecule
• Aromatic amino acids have a cloud of electrons above and below the ring structure
• For cation-pi bonds, a positive charge on the drug/ligand is attracted to the cloud of electrons
• For pi-pi bonds, the clouds of electrons line up side-by-side
• Hydrophobic interactions are driven by chemical groups that prefer to avoid a polar environment
• example of hydrophobic interactions:

  the side chain of leucine prefers to reside near an aromatic group of nicotine and avoid polar groups, including the tertiary amine
• Glycine has no sidechains so will not form any bonds
• alanine, valine, leucine, and isoleucine are aliphatic and will form hydrophobic interactions
• Methionine is aliphatic and has a S, so will interact in:

  • Ion-dopole
  • H-bonds
  • Hydrophobic
• Cysteine is polar with a S so will interact in:

  • ionic
  • ion-dipole
  • H-bonds
• Serine, asparagine, and glutamine are polar and will interact in:

  • Ion-dipole
  • H-bonds
• Threonine is polar and will interact in

  • ion-dipole
  • H-bonds
  • hydrophobic
• Phenylalanine is aromatic and will participate in:

  • pi-cation/pi
  • hydrophobic
• tyrosine and tryptophan are aromatic and will participate in:

  • ion-dipole
  • H-bonds
  • pi-cation/pi
  • hydrophobic
• proline is aromatic and will participate in:

  • H-bonds
  • hydrophobic
• aspartate and glutamate are negatively charged and will participate in:

  • ionic
  • ion-dipole
  • H-bonds
• Lysine, arginine, and histidine are positvely charged and will participate in:

  • ionic
  • ion-dipole
  • H-bonds
  • pi-cation/pi
• The peptide backbone of proteins can form hydrogen bonds with O or N
• proline residues cannot form backbone hydrogen bonds due to the restricted conformation preventing N from interactions