Medicinal Chemistry

Lectures note 3:

DRUG-TARGETS:
INTERACTIONS

3. Drug targets
Binding
regions

Drug Binding
groups

Intermolecular
bonds

Binding site

Binding Drug
site

Drug

Induced fit
Macromolecular target Macromolecular target

Unbound drug Bound drug

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4. Intermolecular bonding forces
4.1 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

• The strength of interaction drops off less rapidly with distance than with other
forms of intermolecular interactions

O
Drug Drug NH3 O
O H3N Target Target
O

4. Intermolecular bonding forces

4.2 Hydrogen bonds
• Vary in strength (16 – 60 kJ mol-1) (distance 1.5 – 2.0 A)

• Weaker than electrostatic interactions but stronger than van der Waals interactions

• A hydrogen bond takes place between an electron deficient hydrogen and an

electron rich heteroatom (N or O)

• The electron deficient hydrogen is usually 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

- + -
- + - Drug Y H X
X H Y Target Target
Drug
HBD HBA HBA HBD

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4. Intermolecular bonding forces
4.2 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

•Oxygen can make two H-bond while amino group only makes one

X H Y X H Y
Hybridised 1s Hybridised
orbital orbital orbital

HBD HBA

4. Intermolecular bonding forces

4.2 Hydrogen bonds

• Examples of strong hydrogen bond acceptors

- carboxylate ion, phosphate ion, tertiary amine

• Examples of moderate hydrogen bond acceptors

- Carbonyl (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

- alkylammonium ion, hydrogen of hydroxyl and amino and amide
groups

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 4. Intermolecular bonding forces
4.2 Hydrogen bonds

• Nitrogen as hydrogen bond acceptors

- Tertiary amine (good HBA)
- Amide (poor HBA)
- Aniline (poor HBA)

• Nitrogen as hydrogen bond Donors

- Positively charged amine (good HBD)
- Primary and secondary are weaker HBD

4. Intermolecular bonding forces

4.3 Van der Waals interactions
• Very weak interactions (2-4 kJ mol-1)

•Occur between hydrophobic regions of the drug and the target

•Interactions drop off rapidly with distance

•Drug must be close to the binding region for interactions to occur

DRUG
Hydrophobic regions

d+ d- Transient dipole on drug d+ d-

van der Waals interaction

d- d+ Binding site

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4. Intermolecular bonding forces
4.4 Dipole-dipole interactions

• 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
d- O Dipole moment

d+ C
R R

Localised
dipole moment R O
C

Binding site Binding site

4. Intermolecular bonding forces

4.5 Ion-dipole interactions

• Stronger than a dipole-dipole interaction

• Strength of interaction falls off less rapidly with distance than for a dipole-dipole
interaction

R O d-
C
d+
R R O d-
C
d+
O H3 N
O C R

Binding site Binding site

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4. Intermolecular bonding forces
4.6 Induced dipole interactions

• e.g. A quaternary ammonium ion and an aromatic ring

d+
+
R N R3 d-

Binding site

5. Desolvation penalties

H O
H O
H H H
O O O

C H C
R R H R R
O H O H O O H O

H C
R R

Binding site Binding site Binding site

Desolvation - Energy penalty Binding - Energy gain

Removing water could be beneficial, but

what about if it is necessary for binding!!
Or for solubility!!

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6. Hydrophobic interactions
• Interactions between the hydrophobic regions 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 Hydrophobic
Drug
regions
Water
Binding site Binding site
Structured water layer Unstructured water
round hydrophobic regions Increase in entropy