Why and where do drugs work

1
Why and where do drugs work?

• Chapter 2

2
Why do drugs work?

• Drugs are chemicals
• Interact with the bodys chemicals
• How/where will they interact?
• - Binding through intermolecular forces

3
Drug targets

• Drug targets are macromolecules
• Drugs generally much smaller than targets
• Drugs interact with targets through IFs
• Binding groups (functional groups on drug) bind
  to binding sites/regions on target
• Most drugs are in equilibrium between being bound
  and unbound to their target

Unbound drug
4
Intermolecular forces

• Electrostatic interactions
• Ion-dipole
• Dipole-dipole
• Hydrogen bonding
• van der Waals/dispersion forces

5
Electrostatic interactions

• Strongest of the intermolecular forces
• Not the same as ionic bonding
• Attraction vs. repulsion
• Strength is inversely proportional to the
  distance between the ions
• Stronger interactions occur in hydrophobic
  environments
• Electrostatic attractions are the most important
  initial interactions as a drug enters the binding
  site

6
Ion-dipole interactions

• Charge on one molecule interacts with the dipole
  of another
• Involved in solvation of ions in water
• Stronger than a dipole-dipole interaction

7
Dipole-dipole interactions

• Occurs if the drug and the binding site have
  dipole moments
• Dipoles align as the drug enters the binding site
• Strength decreases with distance

8
Hydrogen bonds

• Strongest dipole-dipole interaction
• Occurs between an electron-deficient hydrogen and
  an electron-rich heteroatom
• The electron-deficient hydrogen is attached to a
  heteroatom (O or N)
• Hydrogen bond donor (HBD)
• The electron-rich heteroatom is O or N
• Hydrogen bond acceptor (HBA)

9
Hydrogen bonds

• Vary in strength
• The interaction involves orbitals and is
  directional
• Optimum orientation
• X-H bond points directly to the lone pair on Y
• Angle between X, H and Y is 180

10
van der Waals interactions

• Weakest IF
• Occur between hydrophobic regions
• Often hydrophobic pockets on the surface of
  target
• Transient areas of high and low electron
  densities
• Temporary dipoles
• The overall contribution of van der Waals
  interactions can be crucial to binding

DRUG
11
Desolvation penalties

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

O
H
O
H
O
H
Binding site
Binding site
Binding site
Binding Energy gain
Desolvation Energy penalty
12
Desolvation hydrophobic interactions

• Hydrophobic regions of a drug and its target are
  not solvated
• Water molecules interact with each other and form
  an ordered layer next to hydrophobic regions
• Negative entropy
• Hydrophobic interactions between a drug and its
  target free up the ordered water molecules
• Increase in entropy
• Beneficial to binding

Unstructured water Increase in entropy
Structured water layer around hydrophobic regions
13
Where do drugs interact?

• Four main targets
• Lipids
• Carbohydrates
• Nucleic acids
• Proteins

14
I. Lipids

• Structure
• Polar head (hydrophilic)
• Nonpolar tail (hydrophobic)
• Where are lipids typically located?
• Cell membranes of most interest

15
Drug interactions with lipids

• Small number of drugs
• Disrupt lipid structure and kill cell
• 1. Carriers/shuttles
• 2. Tunnels
• Valinomycin
• Antibacterial agent/antibiotic
• Not selective for bacterial cell
• Shuttle hydrophilic material
• out of cell (K)

16
Drug interactions with lipids

• Ergosterol
• Component of fungal cell walls
• Same function as cholesterol in animal cells
• Useful target for antifungal drugs
• Amphotericin B
• Forms hydrophilic tunnel
• Miconazole (Monistat)
• Inhibits synthesis of ergosterol (mechanism
  unknown)
• Primarily used for athletes foot, yeast
  infections

17
II. Carbohydrates

• Empirical formula CH2O
• Energy storage, structural
• Glucose

18
Carbohydrates as drug targets

• Used to tag cells
• Certain cells associated with certain
  carbohydrates
• Glycoproteins, glycosphingolipids
• Interaction of tag with drug to protect or treat
  cells
• More commonly carbohydrates as part of drugs
• Anti-HIV
• Antiherpes
• Antibiotics
• Recent development
• Difficult synthesis
• Varied structures

19
III. Nucleic acids

• Skip this
• IV. Proteins
• Next several chapters