1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter Two THE WHY & THE WHEREFORE: DRUG...

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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal

ChemistryChemistry 3/e 3/e

Chapter TwoChapter Two

THE WHY & THE THE WHY & THE WHEREFORE:WHEREFORE:

DRUG TARGETSDRUG TARGETS

Jony MallikJony MallikM.PharmM.Pharm

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ContentsContents

1. Cell Structure (2 slides)2. Cell Membrane (4 slides)3. Drug Targets (4 slides)4. Intermolecular Bonding Forces

4.1. Electrostatic or ionic bond4.2. Hydrogen bonds (3 slides)4.3. Van der Waals interactions4.4. Dipole-dipole/Ion-dipole/Induced dipole

interactions (4 slides)5. Desolvation penalties6. Hydrophobic interactions7. Drug Targets - Cell Membrane Lipids (2 slides)8. Drug Targets – Carbohydrates (2 slides)

[26 slides]

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1. Cell Structure1. Cell Structure

• Human, animal and plant cells are Human, animal and plant cells are eukaryotic cellseukaryotic cells

• The nucleus contains the genetic The nucleus contains the genetic blueprint for life (DNA)blueprint for life (DNA)

• The fluid contents of the cell are known The fluid contents of the cell are known as the cytoplasmas the cytoplasm

• Structures within the cell are known as Structures within the cell are known as organellesorganelles

• Mitochondria are the source of energy Mitochondria are the source of energy productionproduction

• Ribosomes are the cell’s protein Ribosomes are the cell’s protein ‘factories’‘factories’

• Rough endoplasmic reticulum is the Rough endoplasmic reticulum is the location for protein synthesislocation for protein synthesis

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PhospholipidBilayer

ExteriorHigh [Na+]

InteriorHigh [K+]

2. Cell Membrane2. Cell Membrane

Proteins

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PolarHeadGroup

Hydrophobic Tails


PolarHeadGroup

Hydrophobic Tails

CHCH2 CH2O O

O

P OO

O

CH2CH2NMe3

O O

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PolarHeadGroup

Hydrophobic Tails

CHCH2 CH2O O

O

P OO

O

CH2CH2NMe3

O O


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• The cell membrane is made up of a The cell membrane is made up of a phospholipid bilayerphospholipid bilayer

• The hydrophobic tails interact with each The hydrophobic tails interact with each other by van der Waals interactions and are other by van der Waals interactions and are hidden from the aqueous mediahidden from the aqueous media

• The polar head groups interact with water The polar head groups interact with water at the inner and outer surfaces of the at the inner and outer surfaces of the membranemembrane

• The cell membrane provides a hydrophobic The cell membrane provides a hydrophobic barrier around the cell, preventing the barrier around the cell, preventing the passage of water and polar moleculespassage of water and polar molecules

• Proteins are present, floating in the cell Proteins are present, floating in the cell membranemembrane

• Some act as ion channels and carrier Some act as ion channels and carrier proteinsproteins

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ProteinsProteins ReceptorsReceptorsEnzymesEnzymesCarrier proteinsCarrier proteins

Structural proteins (tubulin)Structural proteins (tubulin)

LipidsLipidsCell membrane lipidsCell membrane lipids

Nucleic acidsNucleic acids DNADNARNARNA

CarbohydratesCarbohydratesCell surface carbohydratesCell surface carbohydrates

Antigens and recognition moleculesAntigens and recognition molecules

3. Drug targets3. Drug targets

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• Drug targets are large molecules - Drug targets are large molecules - macromoleculesmacromolecules

• Drugs are generally much smaller than their Drugs are generally much smaller than their targetstargets

• Drugs interact with their targets by binding to Drugs interact with their targets by binding to binding sitesbinding sites

• Binding sites are typically hydrophobic pockets Binding sites are typically hydrophobic pockets on the surface of macromoleculeson the surface of macromolecules

• Binding interactions typically involve Binding interactions typically involve intermolecular bondsintermolecular bonds

• Most drugs are in equilibrium between being Most drugs are in equilibrium between being bound and unbound to their target bound and unbound to their target

• Functional groups on the drug are involved in Functional groups on the drug are involved in binding interactions and are called binding binding interactions and are called binding groupsgroups

• Specific regions within the binding site that Specific regions within the binding site that are involved in binding interactions are called are involved in binding interactions are called binding regionsbinding regions

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Macromolecular target

Drug

Unbound drug

Macromolecular target

Drug

Bound drug

Bindingsite

Drug

Binding site

Binding regions

Binding groups

Intermolecular bonds


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• Binding interactions usually result in an Binding interactions usually result in an

induced fit where the binding site changes induced fit where the binding site changes

shape to accommodate the drugshape to accommodate the drug

• The induced fit may also alter the overall The induced fit may also alter the overall

shape of the drug targetshape of the drug target

• Important to the pharmacological effect of Important to the pharmacological effect of

the drugthe drug

• Induded Fit and Hexokinase LINKInduded Fit and Hexokinase LINK

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4. 4. Intermolecular bonding forcesIntermolecular bonding forces

4.1 Electrostatic or ionic bond4.1 Electrostatic or ionic bond• Strongest of the intermolecular bonds (20-40 kJ molStrongest of the intermolecular bonds (20-40 kJ mol--

11))• Takes place between groups of opposite chargeTakes place between groups of opposite charge• The strength of the ionic interaction is inversely The strength of the ionic interaction is inversely

proportional to the distance between the two charged proportional to the distance between the two charged groupsgroups

• Stronger interactions occur in hydrophobic Stronger interactions occur in hydrophobic environmentsenvironments

• The strength of interaction drops off less rapidly The strength of interaction drops off less rapidly with distance than with other forms of with distance than with other forms of intermolecular interactionsintermolecular interactions

• Ionic bonds are the most important initial Ionic bonds are the most important initial interactions as a drug enters the binding siteinteractions as a drug enters the binding site Drug

O

O H3N TargetDrug NH3

TargetO

O

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Rimantidine (racemic mixture)

Formulated as Hydrochloride Salt

D44 = Aspartic Acid = Asp44

Side chain is ionized and negatively charged

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4. Intermolecular bonding forces4. Intermolecular bonding forces4.2 Hydrogen bonds4.2 Hydrogen bonds

X HDrug

Y TargetDrug X

TargetHY++

- ---

HBD HBA HBA HBD

• Vary in strengthVary in strength• Weaker than electrostatic interactions but Weaker than electrostatic interactions but

stronger than van der Waals interactionsstronger than van der Waals interactions• A hydrogen bond takes place between an electron A hydrogen bond takes place between an electron

deficient hydrogen and an electron rich deficient hydrogen and an electron rich heteroatom (N or O) heteroatom (N or O)

• The electron deficient hydrogen is usually The electron deficient hydrogen is usually attached to a heteroatom (O or N)attached to a heteroatom (O or N)

• The electron deficient hydrogen is called a The electron deficient hydrogen is called a hydrogen bond donorhydrogen bond donor

• The electron rich heteroatom is called a The electron rich heteroatom is called a hydrogen bond acceptorhydrogen bond acceptor

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YX H YX H

Hybridisedorbital

Hybridisedorbital

1sorbital

HBAHBAHBDHBD

• The interaction involves orbitals and is The interaction involves orbitals and is

directionaldirectional

• Optimum orientation is where the X-H bond Optimum orientation is where the X-H bond

points directly to the lone pair on Y such points directly to the lone pair on Y such

that the angle between X, H and Y is 180that the angle between X, H and Y is 180oo

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• Examples of strong hydrogen bond acceptors Examples of strong hydrogen bond acceptors - carboxylate ion, phosphate ion, tertiary - carboxylate ion, phosphate ion, tertiary

amine amine

• Examples of moderate hydrogen bond Examples of moderate hydrogen bond acceptorsacceptors- carboxylic acid, amide oxygen, ketone, - carboxylic acid, amide oxygen, ketone,

ester, ether, alcoholester, ether, alcohol

• Examples of poor hydrogen bond acceptors Examples of poor hydrogen bond acceptors - sulfur, fluorine, chlorine, aromatic - sulfur, fluorine, chlorine, aromatic

ring, amide nitrogen, aromatic aminering, amide nitrogen, aromatic amine

• Example of good hydrogen bond donorsExample of good hydrogen bond donors- Quaternary ammonium ion- Quaternary ammonium ion

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Sometimes the Hydrogen-bonding networks Can become quite complex

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4. Intermolecular bonding forces4. Intermolecular bonding forces4.3 Van der Waals interactions4.3 Van der Waals interactions

Binding site

DRUG

- +

• Very weak interactions (2-4 kJmolVery weak interactions (2-4 kJmol-1-1))• Occur between hydrophobic regions of the drug Occur between hydrophobic regions of the drug

and the targetand the target• Due to transient areas of high and low electron Due to transient areas of high and low electron

densities leading to temporary dipoles densities leading to temporary dipoles • Interactions drop off rapidly with distanceInteractions drop off rapidly with distance• Drug must be close to the binding region for Drug must be close to the binding region for

interactions to occurinteractions to occur• The overall contribution of van der Waals The overall contribution of van der Waals

interactions can be crucial to bindinginteractions can be crucial to binding

+ -

Hydrophobic regions

Transient dipole on drug+ -

van der Waals interaction

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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 forces4. Intermolecular bonding forces4.4 Dipole-dipole interactions4.4 Dipole-dipole interactions

• Can occur if the drug and the binding site Can occur if the drug and the binding site have dipole momentshave dipole moments

• Dipoles align with each other as the drug Dipoles align with each other as the drug enters the binding siteenters the binding site

• Dipole alignment orientates the molecule in Dipole alignment orientates the molecule in the binding sitethe binding site

• Orientation is beneficial if other binding Orientation is beneficial if other binding groups are positioned correctly with respect groups are positioned correctly with respect to the corresponding binding regionsto the corresponding binding regions

• Orientation is detrimental if the binding Orientation is detrimental if the binding groups are not positioned correctly with groups are not positioned correctly with respect to corresponding binding regionsrespect to corresponding binding regions

• The strength of the interaction decreases The strength of the interaction decreases with distance more quickly than with with distance more quickly than with electrostatic interactions, but less quickly electrostatic interactions, but less quickly than with van der Waals interactionsthan with van der Waals interactions

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Binding site

Localiseddipole moment

Dipole moment

RC

R

O

Binding site

R

CR O

4.4 Dipole-dipole interactions4.4 Dipole-dipole interactions4. Intermolecular bonding forces4. Intermolecular bonding forces

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4. Intermolecular bonding forces4. Intermolecular bonding forces4.4 Ion-dipole interactions4.4 Ion-dipole interactions

• Occur where the charge on one molecule Occur where the charge on one molecule interacts with the dipole moment of anotherinteracts with the dipole moment of another

• Stronger than a dipole-dipole interactionStronger than a dipole-dipole interaction

• Strength of interaction falls off less Strength of interaction falls off less rapidly with distance than for a dipole-rapidly with distance than for a dipole-dipole interactiondipole interaction

C

O

O

Binding siteBinding site

RR

CCRR OO

H3N


RR

CCRR OO

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4. Intermolecular bonding forces4. Intermolecular bonding forces4.4 Induced dipole interactions4.4 Induced dipole interactions

• Occur where the charge on one molecule Occur where the charge on one molecule induces a dipole on anotherinduces a dipole on another

• Occurs between a quaternary ammonium ion and Occurs between a quaternary ammonium ion and an aromatic ringan aromatic ring


RR NN RR33

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RC

R

O

OH

HH H

O

H

H

O

H

H

O

OH

Binding site

Desolvation - Energy penalty Binding - Energy gain

OH

RC

R

O

Binding site

RC

R

O

OH

Binding site

5. Desolvation penalties5. Desolvation penalties• Polar regions of a drug and its target are Polar regions of a drug and its target are

solvated prior to interactionsolvated prior to interaction

• Desolvation is necessary and requires energyDesolvation is necessary and requires energy

• The energy gained by drug-target The energy gained by drug-target interactions must be greater than the energy interactions must be greater than the energy required for desolvationrequired for desolvation

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Unstructured waterUnstructured waterIncrease in entropyIncrease in entropy

DrugDrugDRUGDRUG

Structured water layer Structured water layer round hydrophobic regionsround hydrophobic regions

HydrophobicHydrophobic regionsregionsWaterWater

Binding siteBinding site Binding siteBinding site

DrugDrugDRUGDRUG

BindingBinding

6. Hydrophobic interactions6. Hydrophobic interactions• Hydrophobic regions of a drug and its target are Hydrophobic regions of a drug and its target are

not solvatednot solvated• Water molecules interact with each other and Water molecules interact with each other and

form an ordered layer next to hydrophobic form an ordered layer next to hydrophobic regions - negative entropyregions - negative entropy

• Interactions between the hydrophobic Interactions between the hydrophobic interactions of a drug and its target ‘free up’ interactions of a drug and its target ‘free up’ the ordered water molecules the ordered water molecules

• Results in an increase in entropyResults in an increase in entropy• Beneficial to binding energyBeneficial to binding energy

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Hydrophobic regionHydrophobic region

Drugs acting on cell membrane lipids - Drugs acting on cell membrane lipids - Anaesthetics and some antibioticsAnaesthetics and some antibiotics

Action of amphotericin B (antifungal agent)Action of amphotericin B (antifungal agent) - builds tunnels through membrane and drains cell- builds tunnels through membrane and drains cell

7. Drug Targets - Cell Membrane Lipids7. Drug Targets - Cell Membrane Lipids

HydrophilicHydrophilicHydrophilicHydrophilic

HydrophilicHydrophilic

OOH

HO

OHHOOC

OH

O

Me

OH

OHMe

OH O OH

Me

O

O

HONH2

HO

Me

H

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Polar tunnel formedPolar tunnel formedEscape route for ionsEscape route for ions

CELLMEMBRANE

TUNNEL

HO

HO

HO

HO

HO

HO

HO

HO2C CO2H

Sugar

OH OH

Sugar

HO

HO

HO

HO

HO

HO

HO

OH

OH

OH

OH

OH

OH

OH

Sugar

OH OH

Sugar

HO2C CO2H

OH

OH

OH

OH

OH

OH

OH

7. Drug Targets - Cell Membrane Lipids7. Drug Targets - Cell Membrane Lipids

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8. Drug Targets - Carbohydrates8. Drug Targets - Carbohydrates• Carbohydrates play important roles in cell Carbohydrates play important roles in cell

recognition, regulation and growthrecognition, regulation and growth

• Potential targets for the treatment of Potential targets for the treatment of bacterial and viral infection, cancer and bacterial and viral infection, cancer and autoimmune diseaseautoimmune disease

• Carbohydrates act as antigensCarbohydrates act as antigensCarbohydrate 'tag'

CellCellmembranemembrane

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7. Drug Targets - Carbohydrates7. Drug Targets - Carbohydrates

Ceramide 'anchor'Carbohydrate 'tag'

O

OHO

O

OH

HO

OH

(CH2)12CH3

HN (CH2)16CH3

O

Ceramide unit

SUGARS

Carbohydrates

OH

(CH2)12CH3HO

NH2

Sphingosine

HO (CH2)16CH3

O

Fatty Acid (e.g. Stearic acid)O

OHHO

RO

OH

HO

Carbohydrate (R=various carbohydrate structures)

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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

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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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