patrick an introduction to medicinal chemistry 3/e chapter 7 nucleic acids as drug targets
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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). Contents Part 1: Sections 7.1 - 7.2 (DNA & RNA) 1.Deoxyribonucleic Acid (DNA) 1.1.Primary Structure (6 Slides) - PowerPoint PPT PresentationTRANSCRIPT
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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