Transcript Why and where do drugs work? “Drug targets”

Why and where do
drugs work?
“Drug targets”
Chapter 2
Why do drugs work?
• Drugs are chemicals
– Interact with the body’s chemicals
• How/where will they interact?
- Binding through intermolecular forces
Drug Targets
• Drug targets are large molecules - macromolecules
• Drugs are generally much smaller than their targets
• Drugs interact with their targets by binding to binding sites
• Binding sites are typically hydrophobic pockets on the surface of
macromolecules
• Binding interactions typically involve intermolecular bonds
• Functional groups on the drug are involved in binding interactions
and are called binding groups
• Specific regions within the binding site that are involved in binding
interactions are called binding regions
• Most drugs are in equilibrium between being bound and unbound to
their target
Binding
regions
Drug
Binding
groups
Intermolecular
bonds
Binding site
Binding
site
Drug
Drug
Macromolecular target
Unbound drug
Macromolecular target
Bound drug
Intermolecular binding forces
1-Electrostatic or ionic bond

Strongest of the intermolecular bonds (20-40 kJ mol-1)

Takes place between groups of opposite charge

The strength of the ionic interaction is inversely proportional to the
distance between the two charged groups

Stronger interactions occur in hydrophobic environments

Ionic bonds are the most important initial interactions as a drug enters
the binding site
O
Drug
O
Drug NH3
H3N Target
O
Target
O
2-Hydrogen Bonds

Vary in strength

Weaker than electrostatic interactions but stronger than other IF’s

A hydrogen bond takes place between an electron deficient hydrogen
and an electron rich heteroatom (N or O)

The electron deficient hydrogen is attached to a heteroatom (O or N)

The electron deficient hydrogen is called a hydrogen bond donor

The electron rich heteroatom is called a hydrogen bond acceptor
- +
X H
Drug
Y Target
HBD
HBA
Drug Y
HBA
+ H X
Target
HBD
Hydrogen Bonds

The interaction involves orbitals and is directional

Optimum orientation is where the X-H bond points directly
to the lone pair on Y such that the angle between X, H and
Y is 180o
X
Y
H
Hybridized 1s
orbital
orbital
HBD
Hybridized
orbital
HBA
X
H
Y
Hydrogen Bonds

Examples of strong hydrogen bond acceptors
- carboxylate ion, phosphate ion, tertiary amine

Examples of moderate hydrogen bond acceptors
- carboxylic acid, amide oxygen, ketone, ester, ether,
alcohol

Examples of poor hydrogen bond acceptors
- sulfur, fluorine, chlorine, aromatic ring, amide
nitrogen, aromatic amine

Example of good hydrogen bond donors
- Quaternary ammonium ion
3-Van der Waals Interactions

Very weak interactions (2-4 kJmol-1)

Occur between hydrophobic regions of the drug and the target

Due to transient areas of high and low electron densities leading to
temporary dipoles

Interactions drop off rapidly with distance

Drug must be close to the binding region for interactions to occur

The overall contribution of van der Waals interactions can be crucial
to binding
Hydrophobic regions
+ -
Transient dipole on drug
DRUG
+
-
-
+
van der Waals interaction
Binding site
4-Dipole-dipole interactions

Can occur if the drug and the binding site have dipole
moments

Dipoles align with each other as the drug enters the
binding site

Dipole alignment orientates the molecule in the binding
site

The strength of the interaction decreases with distance
more quickly than with electrostatic interactions, but
less quickly than with van der Waals interactions
Dipole-dipole interactions
- O
+ C
R
Dipole moment
R
Localised
dipole moment
R
C
R
Binding site
Binding site
O
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 of interaction falls off less rapidly with distance than for a
dipole-dipole interaction
R
C
O +
R
R
C
O
O
Binding site
C
O +
R
Binding site
H3N
6-Induced-dipole interactions

Occur where the charge on one molecule induces a dipole
on another

Occurs between a quaternary ammonium ion and an
aromatic ring
+
R
+
NR 3
-
Binding site
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
H
O
H
H
O
H
H
O
O
C
R
R
O
H
H
O
H
O
C
R
R
H
H
C
H
Binding site
O
O
R
Binding site
Desolvation - Energy penalty
R
Binding site
Binding - Energy gain
O
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

Interactions between the hydrophobic interactions of a drug and its
target ‘free up’ the ordered water molecules

Results in an increase in entropy

Beneficial to binding energy
DRUG
Drug
Binding
DRUG
Drug
Binding site
Structured water layer
round hydrophobic regions
Binding site
Unstructured water
Increase in entropy
Hydrophobic
regions
Water
Where do drugs interact?
•
•
Cells
Four main targets:
1.
2.
3.
4.
Lipids
Carbohydrates
Nucleic acids
Proteins
I. Lipids
• What is a lipid?
– Polar head (hydrophilic)
– Nonpolar tail (hydrophobic)
• Where are lipids typically located?
 Cell membranes of most interest
Drug interactions with lipids
•
Small number of drugs
•
Disrupt lipid structure and kill cell
1. Tunnels
2. Carriers/shuttles
•
Amphotericin B
–
Antifungal agent
–
Forms hydrophilic tunnel (Fig. 2.21)
•
Valinomycin
–
Antibacterial agent/antibiotic
–
Not selective for bacterial cell
–
Shuttle hydrophilic material out of cell (K+)
I- Cell Membrane Lipids
Drugs acting on cell membrane lipids - Anaesthetics and some antibiotics
Action of amphotericin B (antifungal agent)
- builds tunnels through membrane and drains cell
Hydrophilic
OH
Hydrophilic
O
HO
O
HOOC
OH
OH
OH
OH
OH
O
Me
OH
Me
H
Hydrophilic
Me
Me
O
NH2 HO
HO
O
Hydrophobic region
I-Cell Membrane Lipids
TUNNEL
HO2C
OH
OH CO2H
Sugar
Sugar
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
Polar tunnel formed
Escape route for ions
CELL
MEMBRANE
Sugar
HO2C
Sugar
OH
OH
CO2H
II. Carbohydrates
• Empirical formula CH2O
• Energy storage, structural
• Glucose:
CHO
H
HO
H OH
OH
H OH
H
H
H
O
HO
H
OH
HO
H
HO
H
H
OH
CH2OH
O
H
OH
HO
H
OH
OH
H
OH
H
II- Carbohydrates
•
Carbohydrates play important roles in cell
recognition, regulation and growth
•
Potential targets for the treatment of bacterial and
viral infection, cancer and autoimmune disease
•
Carbohydrates act as antigens
Carbohydrate 'tag'
Cell
membrane
Carbohydrates as drug targets
• Used to tag cells
– Certain cells associated with certain carbohydrates
– Glycoproteins, glycosphingolipids
– Interaction of tag with drug is used to protect or treat cells
• More commonly: carbohydrates as part of drugs
– Anti-HIV
Carbohydrate 'tag'
– Antiherpes
– Antibiotics
• Recent development
– Difficult synthesis
– Varied structures
Cell
membrane
III. Nucleic acids
IV. Proteins