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Ch1 Part2
Ch1 Part2
Ch1 Part2
Plasma membrane
Phospholipid bilayer
Cytoplasm Nucleus
Proteins
Exterior
High [Na+]
Phospholipid
Bilayer
Interior
High [K+]
CH2CH2NMe3
O
Polar Polar
Head Head O P O
Group Group O
CH2 CH CH2
O O
O O
Hydrophobic Tails
Hydrophobic Tails
Binding
regions
Drug Binding
groups
Intermolecular
bonds
Binding site
Binding Drug
site
Drug
Induced fit
Macromolecular target Macromolecular target
O
Drug Drug NH3 O
O H3N Target Target
O
• Vary in strength
• 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
• 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 H Y X H Y
Hybridised 1s Hybridised
orbital orbital orbital
HBD HBA
• Examples of strong hydrogen bond acceptors
- carboxylate ion, phosphate ion, tertiary amine
DRUG
Hydrophobic regions
- + Binding site
• 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
• Orientation is beneficial if other binding groups are positioned correctly
with respect to the corresponding binding regions
• Orientation is detrimental if the binding groups are not positioned
correctly
• The strength of the interaction decreases with distance more quickly than
with electrostatic interactions, but less quickly than with van der Waals
interactions
- O Dipole moment
+ C
R R
Localised
dipole moment R O
C
R O -
C
+
R R O -
C
+
O H3N
O C R
+
+
R NR 3 -
Binding site
• 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 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
DRUG
Drug
Binding
DRUG Hydrophobic
Drug
regions
Water
Binding site Binding site
Structured water layer Unstructured water
round hydrophobic regions Increase in entropy