Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 2
THE WHY & THE WHEREFORE:
DRUG TARGETS
©1
Contents
1.
2.
3.
4.
5.
6.
7.
8.
Cell Structure (2 slides)
Cell Membrane (4 slides)
Drug Targets (4 slides)
Intermolecular Bonding Forces
4.1.
Electrostatic or ionic bond
4.2.
Hydrogen bonds (3 slides)
4.3.
Van der Waals interactions
4.4.
Dipole-dipole/Ion-dipole/Induced dipole
interactions (4 slides)
Desolvation penalties
Hydrophobic interactions
Drug Targets - Cell Membrane Lipids (2 slides)
Drug Targets – Carbohydrates (2 slides)
[26 slides]
©1
1. Cell Structure
•
Human, animal and plant cells are eukaryotic cells
•
The nucleus contains the genetic blueprint for life (DNA)
•
The fluid contents of the cell are known as the cytoplasm
•
Structures within the cell are known as organelles
•
Mitochondria are the source of energy production
•
Ribosomes are the cell’s protein ‘factories’
•
Rough endoplasmic reticulum is the location for protein
synthesis
©1
2. Cell Membrane
Exterior
High [Na+]
Proteins
Phospholipid
Bilayer
Interior
High [K+]
©1
2. Cell Membrane
CH2CH2NMe3
Polar
Head
Group
Polar
Head
Group
O
O
P
O
O
CH2 CH
O
O
CH2
O
O
Hydrophobic Tails
Hydrophobic Tails
©1
2. Cell Membrane
CH2CH2NMe3
Polar
Head
Group
O
O
P
O
O
CH2 CH
O
O
CH2
O
O
Hydrophobic Tails
©1
2. Cell Membrane
•
The cell membrane is made up of a phospholipid bilayer
•
The hydrophobic tails interact with each other by van der
Waals interactions and are hidden from the aqueous media
•
The polar head groups interact with water at the inner and
outer surfaces of the membrane
•
The cell membrane provides a hydrophobic barrier around
the cell, preventing the passage of water and polar molecules
•
Proteins are present, floating in the cell membrane
•
Some act as ion channels and carrier proteins
©1
©1
3. Drug targets
Proteins
Receptors
Enzymes
Carrier proteins
Structural proteins (tubulin)
Lipids
Cell membrane lipids
Nucleic acids
DNA
RNA
Carbohydrates
Cell surface carbohydrates
Antigens and recognition molecules
©1
3. 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
•
Most drugs are in equilibrium between being bound and unbound
to their target
•
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
©1
3. Drug targets
Binding
regions
Drug
Binding
groups
Intermolecular
bonds
Binding site
Binding
site
Drug
Drug
Macromolecular target
Unbound drug
Macromolecular target
Bound drug
©1
©1
3. Drug targets
•
Binding interactions usually result in an induced fit where the
binding site changes shape to accommodate the drug
•
The induced fit may also alter the overall shape of the drug
target
•
Important to the pharmacological effect of the drug
•
Induded Fit and Hexokinase LINK
©1
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
Stronger interactions occur in hydrophobic environments
The strength of interaction drops off less rapidly with distance than with
other forms of intermolecular interactions
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
©1
Formulated as
Hydrochloride Salt
Side chain is
ionized and
negatively charged
D44 = Aspartic Acid = Asp44
Rimantidine
(racemic mixture)
©1
4. Intermolecular bonding forces
4.2 Hydrogen bonds
•
•
•
•
•
•
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
- +
X H
Drug
Y Target
HBD
HBA
Drug Y
HBA
+ H X
Target
HBD
©1
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
X
Y
H
Hybridised 1s
orbital
orbital
HBD
X
H
Y
Hybridised
orbital
HBA
©1
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
- 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
©1
©1
Sometimes the Hydrogen-bonding networks
Can become quite complex
©1
4. Intermolecular bonding forces
4.3 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
©1
A van der Waals Surface around a small molecule,
Showing potential for van der waals interactions
©1
4. Intermolecular bonding forces
4.4 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
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
©1
4. Intermolecular bonding forces
4.4 Dipole-dipole interactions
- O
+ C
R
Dipole moment
R
Localised
dipole moment
R
O
C
R
Binding site
Binding site
©1
4. Intermolecular bonding forces
4.4 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
H3N
Binding site
©1
4. Intermolecular bonding forces
4.4 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
©1
5. 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
H
C
R
O
R
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
©1
O
6. 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
Hydrophobic
regions
Water
Unstructured water
Increase in entropy
©1
7. Drug Targets - 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
O
Hydrophobic region
NH2 HO
HO
©1
7. Drug Targets - 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
©1
©1
Fungal Drug Targets
©1
8. Drug Targets - 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
©1
7. Drug Targets - Carbohydrates
Ceramide 'anchor'
Carbohydrate 'tag'
HO
O
SUGARS O
O
HO
(CH2)16CH3
HN
O
(CH2)12CH3
OH
Carbohydrates
OH
Ceramide unit
O
HO
RO
HO
HO
(CH2)16CH3
Fatty Acid (e.g. Stearic acid)
O
OH
OH
Carbohydrate
(R=various carbohydrate structures)
NH2
HO
(CH2)12CH3
OH
Sphingosine
©1
©1
©1
Drug Targets: DNA
Link
©1
Assigned Reading
An Introduction to Medicinal Chemistry by Graham Patrick, pp. 1-40.
Goodman and Gilman’s The Pharmacological Basis of Therapeutics,
12th edition, Chapter 3, Pharmacodynamics: Molecular Mechanisms of
Drug Action, pp. 41-72.
Caceres, Rafael Andrade; Pauli, Ivani; Timmers, Luis Fernando Saraiva
Macedo; Filgueira de Azevedo, Walter, Jr. Molecular recognition
models: a challenge to overcome. Current Drug Targets (2008),
9(12), 1077-1083. Link
Hof, Fraser; Diederich, Francois. Medicinal chemistry in academia:
molecular recognition with biological receptors. Chemical
Communications (Cambridge, United Kingdom) (2004), (5),
477-480. Link
©1
Optional Reading
Edelman, Gerald M. Biochemistry and the Sciences of
Recognition. Journal of Biological Chemistry (2004),
279(9), 7361-7369. Link
Babine, Robert E.; Bender, Steven L. Molecular
Recognition of Protein-Ligand Complexes: Applications
to Drug Design. Chemical Reviews (Washington, D.
C.) (1997), 97(5), 1359-1472. Link
©1