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Drug targets
Lipids
Cell membrane lipids
Proteins
Receptors
Enzymes
Carrier proteins
Structural proteins (tubulin)
Nucleic acids
DNA
RNA
Carbohydrates
Cell surface carbohydrates
Antigens and recognition molecules
Cell Structure
Cell Membrane
Proteins
Exterior
High [Na+]
Phospholipid
Bilayer
Interior
High [K+]
Cell Membrane
Polar
Head
Group
CH2CH2NMe3
Polar
Head
Group
O
O
P O
O
CH2 CH
O
O
Hydrophobic Tails
Hydrophobic Tails
CH2
O
Cell Membrane
The polar head groups interact with water at the inner and
outer surfaces of the membrane
Drug targets
Drug targets
Binding
regions
Drug
Binding
groups
Intermolecular
bonds
Binding site
Binding
site
Drug
Drug
Macromolecular target
Unbound drug
Macromolecular target
Bound drug
Drug targets
The induced fit may also alter the overall shape of the drug
target
Drug NH3
O
H3N Target
O
Target
O
r is distance in
(10-10 M)
1390q1q 2
V=
!r
!Y Target
HBD
HBA
!Drug Y
HBA
!+ !H X
Target
HBD
Hybridised 1s
orbital
orbital
HBD
Hybridised
orbital
HBA
DRUG
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 with respect to corresponding binding regions
The strength of the interaction decreases with distance more
quickly than with electrostatic interactions, but less quickly than
with van der Waals interactions
Dipole moment
Localised
dipole moment
R
C
R
Binding site
Binding site
Occur where the charge on one molecule interacts with the dipole
moment of another
Strength of interaction falls off less rapidly with distance than for
a dipole-dipole interaction
R
C
O
+
R
C
O
O
Binding site
O
+
Binding site
H3N
+
NR3
Binding site
Desolvation penalties
O
H
C
R
C
R
H
Binding site
O
R
Binding site
Desolvation - Energy penalty
Binding site
Binding - Energy gain
Hydrophobic interactions
DRUG
Drug
Binding
DRUG
Drug
Binding site
Structured water layer
round hydrophobic regions
Binding site
Unstructured water
Increase in entropy
Hydrophobic
regions
Water
Hydrophobic interactions
A nonpolar solute "organizes" water
The H-bond network of water reorganizes to accommodate the
nonpolar solute
T his is an increase in "order" of water-This is a decrease in
ENTROPY
H
kcal/mol
CH4 in benzene CH4 in wate r -2.8
CH4 in ether CH4 in water
-2.4
CH4 in CCl4 CH4 in water
-2.5
C3H8 liquid C3H8 in water
-1.8
Recall G= H-T S
S
cal/K mol
-18
-19
-18
-23
G
kcal/mol
+2.6
+3.3
+2.9
+5.1
OH
Hydrophilic
O
HO
O
HOOC
OH
OH
OH
OH
OH
Me
OH
Me
H
Hydrophilic
Me
Me
O
NH2 HO
HO
Hydrophobic region
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
CELL
MEMBRANE
Sugar
HO2C
Sugar
OH
OH
CO2H
Cell
membrane
Ceramide 'anchor'
Carbohydrate 'tag'
HO
O
SUGARS O
HO
(CH2)16CH3
HN
O
(CH2)12CH3
OH
Carbohydrates
OH
Ceramide unit
HO
RO
HO
HO
(CH2)16CH3
O
OH
OH
Carbohydrate
(R=various carbohydrate structures)
NH2
HO
(CH2)12CH3
OH
Sphingosine