Ligand-Receptor Interactions & Intermolecular Forces

Week 10-11: Ligand-Receptor Interactions

Learning Outcomes

  • Overview of drugs and their biological targets.
  • Describe intramolecular and intermolecular forces within drug targets.
  • Describe intermolecular forces between drugs and drug targets.

Resources

  • Chemistry for the Biosciences 4th ed. Chapter 4, p. 95-126

Drugs and Drug Targets

  • Drugs interact with specific macromolecular targets due to the underlying molecular basis of disease.
  • Ehrlich, 1900: Concept of 'magic bullet' to target specific bacteria without harming healthy cells.
  • Drug targets include:
    • Receptors: typically on cell membranes, such as GPCRs (G-protein coupled receptors) and ion channels.
    • Enzymes: intracellular.
    • Transporters: extracellular, intracellular.
    • Nucleic acids: nucleus.
  • Important considerations: location, structure, and function of these targets.

Cell Structure

  • Nucleus: Contains the genetic blueprint (DNA).
  • Cytoplasm: Fluid contents of the cell.
  • Plasma membrane: Phospholipid bilayer.

Cell Membrane

  • Composed of a phospholipid bilayer.
  • Hydrophobic tails: Interact via van der Waals interactions, hidden from the aqueous media.
  • Polar head groups: Interact with water at inner and outer surfaces of the membrane.
  • Function: Provides a hydrophobic barrier preventing passage of water and polar molecules.
  • Proteins (ion channels, receptors, enzymes, transport proteins) are embedded in the cell membrane.

Drug Targets

  • Drug targets are large molecules (macromolecules).
  • Drugs are generally much smaller than their targets.
  • Drugs bind to specific binding sites on targets.
  • Binding sites are typically hydrophobic hollows or clefts on the surface of macromolecules.
  • Binding involves intermolecular bonds.
  • Most drugs are in equilibrium between bound and unbound states.
  • Binding groups: Functional groups on the drug involved in binding interactions.
  • Binding regions: Specific regions within the binding site involved in binding interactions.

Drug-Target Interactions

  • Binding interactions usually result in an induced fit, where the binding site changes shape to accommodate the drug.
  • The induced fit may also alter the overall shape of the drug target.

Intermolecular Forces

  • Binding leads to conformational change and activity.
  • Types of intermolecular forces:
    • Hydrogen bond
    • Ionic
    • Van der Waals
    • Dipole-dipole
    • Ion-dipole
    • Induced dipole
    • Hydrophobic interactions
  • Intramolecular forces operate between separate parts of the same molecule.

Intermolecular Bonding Forces

  1. Electrostatic or ionic bonds
  2. Hydrogen bonds
  3. Van der Waals forces
  4. Dipole-dipole
  5. Ion-dipole
  6. Induced-dipole interactions
  7. Hydrophobic interactions

1) Electrostatic or Ionic Bonds

  • Strongest intermolecular bonds (200−400200-400 kJ/mol).
  • Occur between groups of opposite charge.
  • Strength is inversely proportional to the distance between the charged groups.
  • Strength drops off less rapidly with distance compared to other intermolecular interactions.
  • Most important initial interactions as a drug enters the binding site.
  • Example: Drug with H3N+H_3N^+ interacting with target's O−O^- .

Importance of pH and Ionisation

  • Important functional groups involved in ionic bonds:
    • Carboxylic acids (R-COOH)
    • Amines (R-NH2)
  • Consider pKa values for ionizable functional groups, using the Henderson-Hasselbalch equation to estimate the ratio of [A-]/[HA].
  • Formation of salt bridge can occur within protein structure.

pKa Table

  • Illustrates the relative strengths of acids and bases using pKa values.
  • Examples provided with corresponding pKa values, conjugate bases, and classifications as stronger/weaker acids/bases.

Amino Acids

  • Table of common amino acids with their respective pKa1, pKa2, pKa3 (where applicable), and pI (isoelectric point) values.
  • Lists Glycine, Alanine, Valine, Leucine, Isoleucine, Methionine, Proline, Phenylalanine, Tryptophan, Asparagine, Glutamine, Serine, Threonine, Tyrosine, Cysteine, Aspartic acid, Glutamic acid, Lysine, Arginine, and Histidine.

Aspartic Acid Example

  • Illustrates the ionization states of aspartic acid at different pH levels.
  • At low pH (acidic media), the overall charge is +1.
  • At neutral pH, a zwitterionic form exists with an overall charge of 0.
  • At high pH (basic media), the overall charge becomes -2.

2) Hydrogen Bonds

  • Vary in strength, typically 20-40 kJ/mol; weaker than electrostatic but stronger than van der Waals.
  • Occur between an electron-deficient hydrogen and an electron-rich heteroatom (N or O).
  • Hydrogen bond donor (HBD): electron-deficient hydrogen attached to a heteroatom (O or N).
  • Hydrogen bond acceptor (HBA): electron-rich heteroatom.
  • X−H⋅⋅⋅YX - H···Y represents a hydrogen bond between donor X and acceptor Y.

Hydrogen Bonds (cont.)

  • Optimum orientation: Y-H bond points directly to the lone pair on X, angle between X, H, and Y is 180 degrees.

Hydrogen Bonds in DNA

  • Hydrogen bonds join complementary nucleotide bases on opposite strands of DNA.
  • Specific base pairings: Adenine-Thymine, Guanine-Cytosine.
  • Examples show successful and unsuccessful base pairing based on hydrogen bond formation.

Drug-Target Interactions (Hydrogen Bonds)

  • Illustrates hydrogen bond formation between a drug and a target.
  • Examples for strong, moderate, and weak HBAs (hydrogen bond acceptors).

3) Van der Waals Interactions

  • Very weak interactions (2-4 kJ/mol); decreases with distance.
  • Occur between hydrophobic regions of the drug and the target.
  • Transient areas of high and low electron densities cause temporary dipoles.
  • Drug must be close to the binding region for interactions to occur.
  • Overall contribution can be crucial to binding.

4) Dipole-Dipole Interactions

  • Occur if the drug and the binding site have dipole moments.
  • Dipoles align as the drug enters the binding site.
  • Dipole alignment orientates the molecule in the binding site.

4) Dipole-Dipole Interactions (cont.)

  • Orientation is beneficial if other binding groups are positioned correctly.
  • Orientation is detrimental if the binding groups are not positioned correctly.
  • Strength decreases with distance more quickly than electrostatic but less quickly than van der Waals.

5) Ion-Dipole Interactions

  • Occur where the charge on one molecule interacts with the dipole moment of another.
  • Stronger than a dipole-dipole interaction.
  • Strength falls off less rapidly with distance than for dipole-dipole.

6) Induced Dipole Interactions

  • Occur when the charge on one molecule induces a dipole on another.
  • Example: interaction between a quaternary ammonium ion and an aromatic ring.

Desolvation Penalties

  • Polar regions of a drug and its target are solvated prior to interaction.
  • Desolvation is necessary and requires energy.
  • Stabilization energy gained by drug-target interactions must be greater than the energy penalty required for desolvation.

7) Hydrophobic Interactions

  • Hydrophobic regions of a drug target are not solvated.
  • Water molecules interact with each other and form an ordered layer next to hydrophobic regions.
  • Interactions between hydrophobic regions of the drug target 'free up' the ordered water molecules.

Overall IMFs on Protein Structure

  • Fundamentally, drug design takes into account the binding regions of the drug target and what IMF can be exploited between the drug and its target.

Chemistry of Life

  • Proteins: the most popular drug target.
  • Includes receptors, enzymes, and transporters.
  • Protein structure and function: primary structure = amino acid sequence.

Proteins: Secondary Structures

  • Alpha-helices vs beta-sheets
  • Hydrogen bonding between peptide bonds
  • Position of side chains
  • Can be predicted from amino acid sequence

Amino Acids

  • 20 natural amino acids classified as nonpolar (hydrophobic) and polar.
  • Examples of nonpolar amino acids: Alanine, Valine, Leucine, Isoleucine, Methionine, Phenylalanine, Proline, Tryptophan.
  • Examples of polar amino acids: Serine, Threonine, Cysteine, Tyrosine, Asparagine, Glutamine, Aspartate, Glutamate, Lysine, Arginine, Glycine, Histidine.
  • Importance of pKa values for each amino acid.

Proteins: Tertiary Structures

  • The overall 3D shape of a protein.
  • Involves structured vs globular arrangements.
  • Includes covalent bonds, repulsive interactions, van der Waals interactions, hydrogen bonding interactions, and ionic bonding interactions.

Proteins: Quaternary Structures

  • Only for proteins with subunits; involves two or more protein subunits.
  • Post-translational modifications of proteins:
    • Acetylation
    • Glycosylation
    • Phosphorylation
    • Carboxylation, etc.

Post-Translational Modifications

  • Important roles in metabolism.
  • Examples:
    • N-Acetylation
    • Hydroxylation
    • Carboxylation
    • Phosphorylation
    • Glycosylation