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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) ©1 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] ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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' ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1 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 ©1