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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 2 THE WHY & THE WHEREFORE: DRUG TARGETS PowerPoint PPT Presentation


Patrick An Introduction to Medicinal Chemistry 3/e Chapter 2 THE WHY & THE WHEREFORE: DRUG TARGETS. Contents 1.Cell Structure (2 slides) 2.Cell Membrane (4 slides) 3.Drug Targets (4 slides) 4.Intermolecular Bonding Forces 4.1.Electrostatic or ionic bond

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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 2 THE WHY & THE WHEREFORE: DRUG TARGETS

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Patrick

An Introduction to Medicinal Chemistry 3/e

Chapter 2

THE WHY & THE WHEREFORE:

DRUG TARGETS


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Contents

1.Cell Structure (2 slides)

2.Cell Membrane (4 slides)

3.Drug Targets (4 slides)

4.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)

5.Desolvation penalties

6.Hydrophobic interactions

7.Drug Targets - Cell Membrane Lipids (2 slides)

8.Drug Targets – Carbohydrates (2 slides)

[26 slides]


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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


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Proteins

Exterior

High [Na+]

Phospholipid

Bilayer

Interior

High [K+]

2. Cell Membrane


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C

H

C

H

N

M

e

2

2

3

O

Polar

Head

O

P

O

Group

O

C

H

C

H

C

H

2

2

O

O

O

O

Hydrophobic Tails

2. Cell Membrane


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C

H

C

H

N

M

e

2

2

3

O

Polar

Head

O

P

O

Group

O

C

H

C

H

C

H

2

2

O

O

O

O

Hydrophobic Tails

2. Cell Membrane


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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


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3. Drug targets

Proteins

ReceptorsEnzymesCarrier proteinsStructural proteins (tubulin)

Lipids

Cell membrane lipids

Nucleic acids

DNARNA

Carbohydrates

Cell surface carbohydratesAntigens and recognition molecules


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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


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Binding

regions

Drug

Binding

groups

Intermolecular

bonds

Binding site

Drug

Binding

site

Drug

Macromolecular target

Macromolecular target

Bound drug

3. Drug targets

Unbound drug


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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


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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

  • 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


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Formulated as

Hydrochloride Salt

Side chain is

ionized and

negatively charged

Rimantidine

(racemic mixture)

D44 = Aspartic Acid = Asp44


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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


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HBD

HBA

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


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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


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Sometimes the Hydrogen-bonding networks

Can become quite complex


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Hydrophobic regions

Transient dipole on drug

d+

d-

d+

d-

van der Waals interaction

d-

d+

Binding site

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

DRUG


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A van der Waals Surface around a small molecule,

Showing potential for van der waals interactions


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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


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d-

Dipole moment

O

d+

C

R

R

Localised

d

ipole moment

R

O

C

R

Binding site

Binding site

4. Intermolecular bonding forces

4.4 Dipole-dipole interactions


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R

R

O

O

d-

d-

C

C

d+

d+

R

R

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


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N

R

3

d+

+

R

d-

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


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O

O

H

O

C

C

H

O

R

R

R

R

H

H

H

O

O

H

C

R

R

H

H

O

O

H

O

O

H

H

Binding site

Binding site

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

Desolvation - Energy penalty

Binding - Energy gain


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6. Hydrophobic interactions

DRUG

Drug

Binding

DRUG

Hydrophobic

regions

Drug

Water

Binding site

Binding site

  • 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

Structured water layer

round hydrophobic regions

Unstructured water

Increase in entropy


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Hydrophilic

Hydrophilic

Hydrophilic

Hydrophobic region

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


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7. Drug Targets - Cell Membrane Lipids

Polar tunnel formed

Escape route for ions


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Fungal Drug Targets


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Cell

membrane

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


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7. Drug Targets - Carbohydrates


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Drug Targets: DNA

Link


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Assigned Reading

An Introduction to Medicinal Chemistry by Graham Patrick, pp. 1-40.

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


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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


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