Drug Target and Drug Receptor

Interaction
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
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
CH2CH2NMe3
 Some act as ion channels and carrier proteins Polar
O
Head O P O
Group O
Polar
Head CH2 CH CH2
Group O O
O O

Hydrophobic Tails
Hydrophobic Tails
 Drugs and Drug Action

 Definition – Drugs
 Chemicals (not light, sound, radiation, magnetic
field)…… fragrance?

 Prevent disease or assist in restoring health

 History
 Originated from natural products

 Examples include opium, belladonna, cinchona,

marijuana, digitalis, quinine, ………….

 First use of synthetic organics …… ether and

chloroform for anesthesia in 1830s

 Structural derivatives …

5
 Drugs and Drug Action

 Drug Action
 Why do drugs work?
‘the hydrophobic effect?’ …. Lipophilicity was thought to be important
‘the medium effect?’ … generally changed conditions
‘the receptor effect?’ … Langley and Ehrlich’s hypothesis (1905)

 The Receptor Hypothesis

 Certain cells contain receptive substances that served
as hosts for the drug molecules to bind

 Example: pilocarpine was selective and potent for

excitation of parasympathetic nervous system, while
atropine was capable of blocking this effect! …… both
interact with same component of the cell

 ‘receptive’ substance  ‘receptor’

 A macromolecule that recognizes ‘drugs’ through

precise physicochemical and steric interactions
6
 Drugs and Drug Action

 Receptor
 Most drugs work through a receptor
e.g., testosterone or steroidal sex hormones; calcium channel blockers;
growth factors; etc.
 Few drugs work without a receptor being involved
e.g., EDTA (for lead poisoning); Mg(OH)2 for gastric acidity; mannitol
for diuretic; etc.
 Types of receptors
Membrane-bound
A. Transcription Factors (e.g.,
steroids, vitamin D, retinoids)
B. Ligand Gated Ion Channels
(e.g., GABAA, glutamate,
aspartate, glycine, etc)
C. G-Protein Coupled Receptors
(GPCRs) (e.g.,
neurotransmitters)
D. Enzyme-linked Receptors (e.g.,
kinases)
E. Protease-Activated Receptors
(e.g., thrombin-cleavage …;
TNFa-converting enzyme)

7
 Drugs and Drug Action
 Typical Structure of a Receptor

8
 Drugs and Drug Action

 Definition of a receptor is changing!

 Free floating enzymes …… trypsin, thrombin, etc.
 DNA and RNA …… cisplatin
 Cell surface carbohydrates …… proteoglycans22

 Drug targets
 Cellular receptors (52%)
 Enzymes (28%)
 Hormones and factors (11%)
 DNA (2%)
 Unknown (7%)

(from Drew, J. (2000) Science 287, 1962)

9
 Theory of Drug Action

 Fischer’s ‘Lock and Key’ Hypothesis

 Every ‘lock’ has its own ‘key’

 If the ‘key’ is not precise, the ‘lock’ does not open
 The ‘drug’ is the key that has to fit the target specifically and
productively

10
 Theory of Drug Action

 Corollary of ‘Lock & Key’ Hypothesis

O
CH3 OH CH3 CH3 OH
C CH

HO
HO HO

OH
O

HO O O

O
H3C CH3 OH
CH2 N CH3 H2C
CH3
CH2
HO H3C

 Does not explain why some ‘keys’ open doors partially?

…… e.g., partial agonists or antagonists
11
 Theory of Drug Action
 Koshland’s ‘Induced-Fit’ Hypothesis

 At least two steps …… e.g., step 1 is initial binding and step 2 is a change
in structure of the receptor (and/or drug)

 Receptor is flexible! …… can wrap around the drug …… the zipper model
is extreme case of induced-fit

 All intermediate cases do exist in nature 12

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
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
3. Drug targets
Binding
regions

Drug Binding
groups

Intermolecular
bonds

Binding site

Binding Drug
site

Drug

Macromolecular target Macromolecular target

Unbound drug Bound drug

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
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 Drug NH3 O
O H3N Target Target
O
 Formulated as
Hydrochloride Salt

Side chain is
ionized and Rimantidine
negatively charged (racemic mixture)

D44 = Aspartic Acid = Asp44

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

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

- 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
Sometimes the Hydrogen-bonding networks
Can become quite complex
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 DRUG

+ - Transient dipole on drug
+ -
van der Waals interaction

- +
Binding site
A van der Waals Surface around a small molecule,
Showing potential for van der waals interactions
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
4. Intermolecular bonding forces
4.4 Dipole-dipole interactions

- O Dipole moment

+ C
R R

Localised
dipole moment R O
C

Binding site Binding site

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 O -
C
+
R R O -
C
+
O H3N
O C R

Binding site Binding site

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
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 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

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 Hydrophobic
Drug
regions
Water
Binding site Binding site
Structured water layer Unstructured water
round hydrophobic regions Increase in entropy
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
HO O Me

OH
O OH OH OH OH O OH
HOOC Me
H
Hydrophilic Me
Me
O
O Hydrophobic region
NH2 HO

HO
7. Drug Targets - Cell Membrane Lipids
TUNNEL

HO2C OH OH CO2H

Sugar Sugar

OH HO

OH HO

OH HO
OH HO Polar tunnel formed
OH HO Escape route for ions
OH HO

OH HO

CELL
MEMBRANE

OH HO

OH HO
OH HO
OH HO
OH HO

OH HO

OH HO

Sugar Sugar
HO2C OH CO2H
OH
Fungal Drug Targets
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
7. Drug Targets - Carbohydrates

Carbohydrate 'tag' Ceramide 'anchor'

HO
O
SUGARS O
O
HN (CH2)16CH3
HO O (CH2)12CH3
OH
OH

Carbohydrates Ceramide unit

O
HO
HO (CH2)16CH3
RO
O Fatty Acid (e.g. Stearic acid)

HO OH NH2
OH HO (CH2)12CH3
Carbohydrate
(R=various carbohydrate structures) OH
Sphingosine
 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.

Hof, Fraser; Diederich, Francois. Medicinal chemistry in academia:

molecular recognition with biological receptors. Chemical
Communications (Cambridge, United Kingdom) (2004), (5),
477-480.
Optional Reading

Edelman, Gerald M. Biochemistry and the Sciences of

Recognition. Journal of Biological Chemistry (2004),
279(9), 7361-7369.

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.