patrick an introduction to medicinal chemistry 3/e chapter 7 nucleic acids as drug targets

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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal

ChemistryChemistry 3/e 3/e

Chapter 7 Chapter 7

NUCLEIC ACIDS AS DRUG NUCLEIC ACIDS AS DRUG TARGETSTARGETS

Part 1: Sections 7.1 - 7.2 (DNA & RNA)Part 1: Sections 7.1 - 7.2 (DNA & RNA)

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ContentsContents

Part 1: Sections 7.1 - 7.2 (DNA & RNA)

1. Deoxyribonucleic Acid (DNA)1.1. Primary Structure (6 Slides)1.2. Secondary Structure - Double Helix (4 slides)1.3. Tertiary Structure

2. Ribonucleic Acid (RNA)2.1. Primary structure 2.2. Secondary structure 2.3. Tertiary structure (2 slides)2.4. Transcription2.5. Translation - protein synthesis (7 slides)

[25 slides]

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OP

OH

O

O

P

OH

O

O O

OP

OH

O

O BaseO

Base

O

O

BasePO

OH

O

BaseO

O

5' end

3' End

1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)

5' end

1'

3'

5'

3' End

3'

Sugar phosphate backbone

N

NH

N

N

N

H

OH H

OH

H

CH2

CH2

HH

HHO

OP

OH

O

O

N

OH H

H

H

CH2

CH2

HH

HHO

O

PO

OH

O

N

N

N

N

N

NH

NH2

OPO

O

OH

PO

OH

O

NH2

O

O

NH2

O

O

Me

H

H

H

1.1 Primary Structure1.1 Primary Structure

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1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)

Building blocks - NucleotidesBuilding blocks - Nucleotides

Deoxyadenosinephosphate

N

N N

N

NH2

H

O

H H

HO H

H

HO3PO

Deoxyguanosinephosphate

H

HHO

HH

O

N

H

O

NN

NH2N

HO3PO

Deoxythymidinephosphate

O

HN

N

H

CH3

O

O

H H

HO H

H

HO3PO

Deoxycytidinephosphate

H

HHO

HH

O

NH2

H

N

N

O

HO3PO

1.1 Primary Structure1.1 Primary Structure

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BaseBase

PhosphatePhosphate

SugarSugar

1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)

Nucleotide = Phosphate + sugar + baseNucleotide = Phosphate + sugar + base

Deoxyadenosinephosphate

N

N N

N

NH2

H

O

H H

HO H

H

HO3PO

1.1 Primary Structure1.1 Primary Structure

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1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)

Nucleosides = Sugar + BaseNucleosides = Sugar + Base

Deoxyadenosine

N

N N

N

NH2

H

O

H H

HO H

H

HO

Deoxyguanosine

H

HHO

HH

O

N

H

O

NN

NH2NHO

Deoxythymidine

O

HN

N

H

CH3

O

O

H H

HO H

H

HO

Deoxycytidine

H

HHO

HH

O

NH2

H

N

N

OHO

1.1 Primary Structure1.1 Primary Structure

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1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)

Nucleic acid basesNucleic acid bases

Purines Pyrimidines

SugarSugar O OH

HHH

HOH

HOCH2

H

Adenine

NH2

N

NH

N

N

12

3456 7

89

Guanine

H2N

HN

N NH

N

O

12 3 4

56

78

9

Cytosine

NH2

N

NH

O1

23

4 5

6

Thymine

O

HN

NH

CH3

O

123

45

6

DeoxyriboseDeoxyribose

1.1 Primary Structure1.1 Primary Structure

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1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)1.1 Primary Structure1.1 Primary Structure

Note:Note: Sugar phosphate backbone is constantSugar phosphate backbone is constantBases attached in apparently random orderBases attached in apparently random order

N

NH

N

N

N

H

OH H

OH

H

CH2

CH2

HH

HHO

OP

OH

O

O

N

OH H

H

H

CH2

CH2

HH

HHO

O

PO

OH

O

N

N

N

N

N

NH

NH2

OPO

O

OH

PO

OH

O

NH2

O

O

NH2

O

O

Me

H

H

H

Adenine (A)

Cytosine (C)

Guanine (G)

Thymine (T)

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1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)

• Sugar phosphate backbone is ionised Sugar phosphate backbone is ionised and faces outward (favourable and faces outward (favourable interactions with water)interactions with water)

• Nucleic acid bases point inward and Nucleic acid bases point inward and pair up A-T or G-Cpair up A-T or G-C

• Purine pairs with pyrimidine - Purine pairs with pyrimidine - constant diameter to helixconstant diameter to helix

• Base bairs are stacked (vdw Base bairs are stacked (vdw interactions between pairs)interactions between pairs)

• Chains are complementary Chains are complementary

T

o34A

o10A

DNA DOUBLE HELIX

TAG

C

ATC

GCTA

ATCG

A

T AT A

TA

TAT A

G C

C

T ATA

A

G C

T

CGCG

ATAT

Majorgroove

Minor groove

G

G

1.2 Secondary Structure - Double Helix1.2 Secondary Structure - Double Helix

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N

N

N

NH2N

N

NH

O

O

Me

O

OP

O

O

OO

P

O

O

O

HN

N

N

NO

H2N

O

P

O

OO

N

N

NH2

OO

OP

O

O

OO

P

O

O

O

O

P

O

OO

3'

3'

5'

5'

5'

5'

3'

3'

Thymine Adenine

Cytosine Guanine

1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)

Base PairingBase PairingG-C base pairing involves 3 H-bondsG-C base pairing involves 3 H-bondsA-T base pairing involves 2 H-bondsA-T base pairing involves 2 H-bonds

T

o34A

o10A

DNA DOUBLE HELIX

TAG

C

ATC

GCTA

ATCG

A

T AT A

TA

TAT A

G C

C

T ATA

A

G C

T

CGCG

ATAT

Majorgroove

Minor groove

G

G

1.2 Secondary Structure - Double Helix1.2 Secondary Structure - Double Helix

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1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)

DNA Double Helix

Replication

NewDNA

chains

TemplateTemplate

New DNAchains

DNA Daughter helices

1.2 Secondary Structure - Double Helix1.2 Secondary Structure - Double Helix

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1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)1.2 Secondary Structure - Double Helix1.2 Secondary Structure - Double Helix

AX

Trinucleotide

Approach of trinucleotideApproach of trinucleotide

5'

3'

Templatechain

A

C

T

C

G

5'

3'

Growing chain

G

C

5'

3'

Templatechain

A

5'

X

Growing chain

Base pairingBase pairing

A

C

T

C

G

G

C3'

5'

3'

Templatechain

5'

Growing chain

Enzyme catalysed 'splicing'Enzyme catalysed 'splicing'

X-A

C

T

C

G

G

C

A 3'

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1. DEOXYRIBONUCLEIC ACID (DNA)1. DEOXYRIBONUCLEIC ACID (DNA)1.3 Tertiary Structure1.3 Tertiary Structure

• Double helix coils into a 3D shape - supercoilingDouble helix coils into a 3D shape - supercoiling

• Double helix has to unravel during replication Double helix has to unravel during replication

• Unravelling leads to strainUnravelling leads to strain

• Relieved by enzyme catalysed cutting and repair of DNA Relieved by enzyme catalysed cutting and repair of DNA chainchain

• Important to the activity of the quinolone and fluoroquinolone Important to the activity of the quinolone and fluoroquinolone antibacterial agents which act as enzyme inhibitorsantibacterial agents which act as enzyme inhibitors

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2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)2.1 Primary structure2.1 Primary structure

• Similar to DNA with the following exceptionsSimilar to DNA with the following exceptions

• Ribose is used instead of deoxyriboseRibose is used instead of deoxyribose

• Uracil is used rather than thymineUracil is used rather than thymine

UracilUracil

HN

NH

O

O

RiboseRibose

O OH

HHH

OHOH

HOCH2

H

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2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)2.2 Secondary structure2.2 Secondary structure

• Single strandedSingle stranded

• Some regions of helical secondary structure exist due to base Some regions of helical secondary structure exist due to base pairing within the same strand (see t-RNA)pairing within the same strand (see t-RNA)

• Adenine pairs to uracil; guanine pairs to cytosineAdenine pairs to uracil; guanine pairs to cytosine

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2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)

• Three types of RNA are involved in protein synthesis:Three types of RNA are involved in protein synthesis:

• Messenger RNA (mRNA)Messenger RNA (mRNA) Relays the code for a protein from DNA to the protein Relays the code for a protein from DNA to the protein production site production site

• Transfer RNA (tRNA)Transfer RNA (tRNA) The adapter unit linking the triplet code on mRNA to specific The adapter unit linking the triplet code on mRNA to specific amino acidsamino acids

• Ribosomal RNA (rRNA)Ribosomal RNA (rRNA) Present in ribosomes (the production site for protein synthesis). Present in ribosomes (the production site for protein synthesis). Important both structurally and catalyticallyImportant both structurally and catalytically

2.3 Tertiary structure2.3 Tertiary structure

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mI MethylinosineI InosineUH2 DihydrouridineT RibothymidinePs PseudouridinemG Methylguanosinem2G Dimethylguanosine

2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)2.3 Tertiary structure2.3 Tertiary structure

Anticodon Anticodon - the 3 bases are specific for the attached amino acid- the 3 bases are specific for the attached amino acid- base pair to the complementary triplet code on m-- base pair to the complementary triplet code on m-RNA (the codon)RNA (the codon)

Yeast alanine-tRNAYeast alanine-tRNA

AMINOACID

C

G

G

C

C

G

G

C

C

G

C

G

G

C

G

C

A

U

G C

GC GG UGG C

GPs

C

UmIU

CIG

UH2G

GAGGC

CUCm2G

UH2

CG

G

G

A

UH2

U

A

G

C

G

A

Ps

U

T

U

mGU

A

C

CA

CA

UC

C

U

3'pend

5'pend

ANTICODON

Base Pairing

ACG

Aminoacid

t-RNA

Anticodonbinding regionfor m-RNA

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2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)2.4 Transcription2.4 Transcription

The copying of a segment of DNA which codes for a specific proteinThe copying of a segment of DNA which codes for a specific protein

DNA double helixDNA double helix DNA unravelledDNA unravelledto reveal geneto reveal gene

AGATAC

CAGGGAAT

TCTATG

GTCCCTTA

TranscriptionTranscription

mRNA

AGATAC

CAGGGAAT

UCUAUG

GUCCCUUA

TCTATG

GTCCCTTA

mRNAmRNA

UCUAUG

GUCCCUUA

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2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)

Ribosome

60S

40S

A-siteP-site

mRNAmRNA CGA CAU GUCCGA CAU GUC

2.5 Translation - protein synthesis2.5 Translation - protein synthesis

GrowingGrowingprotein chainprotein chain

GCUGCU GCAGCA

HisHis

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2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)

Ribosome

60S

40S

A-siteP-site

mRNAmRNA CGA CAU GUCCGA CAU GUC

2.5 Translation - protein synthesis2.5 Translation - protein synthesis

Protein chainProtein chaintransferredtransferred

GCUGCU GCAGCA

HisHisOHOH

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2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)

Ribosome

60S

40S

A-siteP-site

mRNAmRNA CGA CAU GUCCGA CAU GUC

2.5 Translation - protein synthesis2.5 Translation - protein synthesis

Protein chainProtein chaintransferredtransferred

GCAGCA

HisHis

GCUGCU

OHOH

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2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)

Ribosome

60S

40S

A-siteP-site

mRNAmRNA CGA CAU GUCCGA CAU GUC

2.5 Translation - protein synthesis2.5 Translation - protein synthesis

Protein chainProtein chaintransferredtransferred

GCAGCA

HisHis

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2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)

Ribosome

60S

40S

A-siteP-site

mRNAmRNA CGA CAU GUCCGA CAU GUC

2.5 Translation - protein synthesis2.5 Translation - protein synthesis

Protein chainProtein chaintransferredtransferred

GCAGCA

HisHis

CAGCAG

ValVal

tRNAtRNA

TranslocationTranslocation

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O

H H

HO O

Adenine

H

O P

O

t RNA

OH

O

H

CO

C HR'

NH2

C

NH

R H

CO

O

H

P O

OH

O

t RNA

O

H

Adenine

HO

HH

O

PEPTIDE

2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)2.5 Translation - protein synthesis2.5 Translation - protein synthesis

Transfer of growing peptidechain to nextamino acid

O

H H

HO OH

Adenine

H

O P

O

t RNA

OH

O

H

NH

PEPTIDE

NH

CO

C HR

CR' H

CO

O

H

P O

OH

O

t RNA

O

H

Adenine

HO

HH

O

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DNA

Nucleus

2. RIBONUCLEIC ACID (RNA)2. RIBONUCLEIC ACID (RNA)

Transcription

mRNA

mRNA

tRNA

Amino acid

Translation

2.5 Translation - protein synthesis2.5 Translation - protein synthesisOverviewOverview

Ribosome

Protein