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Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 7
NUCLEIC ACIDS AS DRUG
TARGETS
Part 1: Sections 7.1 - 7.2 (DNA & RNA)
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Contents
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. Transcription
2.5. Translation - protein synthesis (7 slides)
[25 slides]
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1. DEOXYRIBONUCLEIC ACID (DNA)
1.1 Primary Structure
NH2
5' end
N
O
O P O
OH
5'
N
CH2
O
O P O
N
O
H
H
5' end
N
H
1'
NH2
3' H H
N
P
O CH2
OH
OH
O P O
O
OH
H
H
H
O
H
N
O
NH
N
P
Base
O
O
O
H
O
O
N
O
O
Base
O CH2
OH
N
NH2
H
O
OH
H
H
H
O
Me
NH
O
N
P
Base
O P O
O
H
O
O
O CH2
OH
H
H
O
O P O
Base
O
OH
H
3' H
O
O
H
3' End
3' End
Sugar phosphate backbone
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1. DEOXYRIBONUCLEIC ACID (DNA)
1.1 Primary Structure
Building blocks - Nucleotides
O
NH2
N
N
N
N
HO3PO
H
Deoxyadenosine
phosphate
O
H
H
H
H
Deoxyguanosine
phosphate
N
HO3PO
O
O
H
HO
N
N
HO3PO
H
H
H
HO
O
O
H
CH3
HN
N
N
O
H
N
N
H2N
HO3PO
NH2
O
H
H
H
H
HO
H
Deoxythymidine
phosphate
H
H
H
HO
H
Deoxycytidine
phosphate
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1. DEOXYRIBONUCLEIC ACID (DNA)
1.1 Primary Structure
Nucleotide = Phosphate + sugar + base
NH2
N
N
Deoxyadenosine
phosphate
Base
N
N
HO3PO
O
Phosphate
H
H
H
H
HO
Sugar
H
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1. DEOXYRIBONUCLEIC ACID (DNA)
1.1 Primary Structure
Nucleosides = Sugar + Base
NH2
O
N
N
N
N
HO
O
H
N
N
O
H
H
Deoxyadenosine
O
H
H
H
H
Deoxyguanosine
N
HO
O
H
HO
N
N
HO
H
H
CH3
HN
O
H
HO
N
N
H2N
HO
NH2
O
O
H
H
HO
H
H
H
Deoxythymidine
H
H
HO
H
H
Deoxycytidine
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1. DEOXYRIBONUCLEIC ACID (DNA)
1.1 Primary Structure
Sugar
HOCH2
Deoxyribose
H
OH
O
H
H
OH
Nucleic acid bases
NH2
N1
2
6
3
N
H
H
NH2
O
N
5 7
4 9
HN1
8
2
N
H
H2N
Adenine
6
3
5 7
4 9
N
Guanine
Purines
N
N
H
N3
8
2
O
O
4
5
1
6
O
N
H
Cytosine
4
HN3
2 1
N
H
Thymine
Pyrimidines
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CH3
5
6
1. DEOXYRIBONUCLEIC ACID (DNA)
1.1 Primary Structure
NH2
N
O
O P O
OH
N
CH2
N
O
H
H
H
H
NH2
H
N
O
O
Adenine (A)
N
P
N
O CH2
OH
Cytosine (C)
O
O
H
H
H
H
H
O
N
O
NH
N
O
P
O
N
CH2
O
H H
H
H
H
Me
O
OH
O
NH
N
O
P O
CH2
OH
H
Guanine (G)
NH2
O
Thymine (T)
O
H
H
H
H
Note: Sugar phosphate backbone is constant
Bases attached in apparently random order
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1. DEOXYRIBONUCLEIC ACID (DNA)
1.2 Secondary Structure - Double Helix
•
o
10A
G C
AT
Major
groove
TA
T A
G C
G C
TA
T A
Minor
groove
T A
AT
AT
T A
C G
G C
TA
T A
•
o
34A
•
G C
GC
GC
T A
A T
C G
•
TA
T A
•
Sugar phosphate backbone is ionised
and faces outward (favourable
interactions with water)
Nucleic acid bases point inward and
pair up A-T or G-C
Purine pairs with pyrimidine constant diameter to helix
Base bairs are stacked (vdw
interactions between pairs)
Chains are complementary
DNA DOUBLE HELIX
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1. DEOXYRIBONUCLEIC ACID (DNA)
1.2 Secondary Structure - Double Helix
Thymine
o
10A
Me
G C
AT
Major
groove
H2N
O P
N
O
O P
O
TA
T A
G C
G C
T A
AT
AT
T A
C G
G C
TA
T A
G C
GC
GC
T A
A T
C G
TA
T A
DNA DOUBLE HELIX
o
34A
NH
O
O
5'
TA
T A
Minor
groove
O
Adenine
3'
N
N
O
5'
N
N
O
O
O
O
O P
O
N
O
O
5'
NH2
3'
O
O P
O
O
N
N
HN
3'
O
P
O
O
N
N
O
3'
O
Cytosine
H2N
Guanine
5'
O
O P
O
O
O
Base Pairing
G-C base pairing involves 3 H-bonds
A-T base pairing involves 2 H-bonds
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1. DEOXYRIBONUCLEIC ACID (DNA)
1.2 Secondary Structure - Double Helix
New
DNA
chains
Template
DNA
Double Helix
New
DNA
chains
Template
Replication
DNA
Daughter helices
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1. DEOXYRIBONUCLEIC ACID (DNA)
1.2 Secondary Structure - Double Helix
5'
3'
Trinucleotide
X
A
Template
chain
5'
Template
chain
5'
Template
chain
A
A
A
C
C
C
T
T
A
T
A
C
G
C
G
G
C
G
C
C
G
G
C
3'
5'
Growing
chain
Approach of trinucleotide
X
3'
3'
5'
Growing
chain
Base pairing
3'
X3'
5'
Growing
chain
Enzyme catalysed 'splicing'
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1. DEOXYRIBONUCLEIC ACID (DNA)
1.3 Tertiary Structure
•
Double helix coils into a 3D shape - supercoiling
•
Double helix has to unravel during replication
•
Unravelling leads to strain
•
Relieved by enzyme catalysed cutting and repair of DNA
chain
•
Important to the activity of the quinolone and fluoroquinolone
antibacterial agents which act as enzyme inhibitors
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2. RIBONUCLEIC ACID (RNA)
2.1 Primary structure
•
Similar to DNA with the following exceptions
•
Ribose is used instead of deoxyribose
•
Uracil is used rather than thymine
O
HOCH2 O
H
OH
HN
H
H
H
OH
OH
Ribose
O
N
H
Uracil
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2. RIBONUCLEIC ACID (RNA)
2.2 Secondary structure
•
Single stranded
•
Some regions of helical secondary structure exist due to base
pairing within the same strand (see t-RNA)
•
Adenine pairs to uracil; guanine pairs to cytosine
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2. RIBONUCLEIC ACID (RNA)
2.3 Tertiary structure
•
Three types of RNA are involved in protein synthesis:
•
Messenger RNA (mRNA)
Relays the code for a protein from DNA to the protein
production site
•
Transfer RNA (tRNA)
The adapter unit linking the triplet code on mRNA to specific
amino acids
•
Ribosomal RNA (rRNA)
Present in ribosomes (the production site for protein synthesis).
Important both structurally and catalytically
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2. RIBONUCLEIC ACID (RNA)
2.3 Tertiary structure
Base Pairing
mI Methylinosine
I
Inosine
UH2 Dihydrouridine
T
Ribothymidine
Ps
Pseudouridine
mG Methylguanosine
m2G Dimethylguanosine
3'p
end
A
C
C
A
C
C
U
G
C
U
C
AMINO
AC ID
5'p
end
G
G
G
C
G
U
A U
U UA
G
G
G
A G G C C
UH2
C G C G mGU
G
C
U C C G G
G C G C m2G
G
C
T PsC
A
G UH2
C
G A UH2
G
U
A
C
G
C
G
C
G
Ps
U
U
mI
I
C
G
Yeast alanine-tRNA
ANTICODON
Anticodon
- the 3 bases are specific for the attached amino acid
- base pair to the complementary triplet code on mRNA (the codon)
Amino
acid
t-RNA
AC G
Anticodon
binding region
for m-RNA
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2. RIBONUCLEIC ACID (RNA)
2.4 Transcription
The copying of a segment of DNA which codes for a specific protein
G
U
A
U
C
U
G
U
C
C
C
U
U
A
mRNA
G
T
A
T
C
T
G
T
C
C
C
T
T
A
DNA double helix
C
A
T
A
G
A
C
A
G
G
G
A
A
T
DNA unravelled
to reveal gene
G
T
A
T
C
T
G
T
C
C
C
T
T
A
G
U
A
U
C
U
G
U
C
C
C
U
U
A
C
A
T
A
G
A
C
A
G
G
G
A
A
T
mRNA
Transcription
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2. RIBONUCLEIC ACID (RNA)
2.5 Translation - protein synthesis
Growing
protein chain
His
Ribosome
60S
mRNA
P-site A-site
GCU GCA
CGA CAU GUC
40S
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2. RIBONUCLEIC ACID (RNA)
2.5 Translation - protein synthesis
Protein chain
transferred
OH
His
Ribosome
60S
mRNA
P-site A-site
GCU GCA
CGA CAU GUC
40S
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2. RIBONUCLEIC ACID (RNA)
2.5 Translation - protein synthesis
OH
Protein chain
transferred
His
GCU
Ribosome
60S
mRNA
P-site A-site
GCA
CGA CAU GUC
40S
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2. RIBONUCLEIC ACID (RNA)
2.5 Translation - protein synthesis
Protein chain
transferred
His
Ribosome
60S
mRNA
P-site A-site
GCA
CGA CAU GUC
40S
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2. RIBONUCLEIC ACID (RNA)
2.5 Translation - protein synthesis
Protein chain
transferred
His
Val
tRNA
Ribosome
60S
mRNA
P-site A-site
GCA CAG
CGA CAU GUC
40S
Translocation
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2. RIBONUCLEIC ACID (RNA)
2.5 Translation - protein synthesis
PEPTIDE
NH2
NH
R' C H
O C
R C H
O C
HO
H
H
Adenine
HO
H
H
O
H
O
H
O
OH
P O
Adenine
O
H
O
H
O
OH
O
O
t RNA
t RNA
Transfer of
growing peptide
chain to next
amino acid
PEPTIDE
P O
NH
R C H
O C
NH
HO
H
H
Adenine
R' C H
O C
OH
H H
O
OH
O P O
O
t RNA
HO
H
H
Adenine
O
H H
O
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O
OH
P O
O
t RNA
2. RIBONUCLEIC ACID (RNA)
2.5 Translation - protein synthesis
Overview
mRNA
Ribosome
Amino acid
DNA
tRNA
mRNA
Translation
Transcription
Nucleus
Protein
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