Patrick An Introduction to Medicinal Chemistry 3/e Chapter 7 NUCLEIC ACIDS AS DRUG TARGETS

1. Patrick An Introduction to Medicinal Chemistry 3/e Chapter 7 NUCLEIC ACIDS AS DRUG TARGETS Part 1: Sections 7.1 - 7.2 (DNA & RNA)

2. 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]

3. 5' 1' 3' 3' 3' End 1. DEOXYRIBONUCLEIC ACID (DNA) 1.1 Primary Structure 5' end Sugar phosphate backbone

4. Deoxythymidine phosphate Deoxyadenosine phosphate Deoxyguanosine phosphate Deoxycytidine phosphate 1. DEOXYRIBONUCLEIC ACID (DNA) 1.1 Primary Structure Building blocks - Nucleotides

5. Base Deoxyadenosine phosphate Phosphate Sugar 1. DEOXYRIBONUCLEIC ACID (DNA) 1.1 Primary Structure Nucleotide = Phosphate + sugar + base

6. Deoxyadenosine Deoxyguanosine Deoxythymidine Deoxycytidine 1. DEOXYRIBONUCLEIC ACID (DNA) 1.1 Primary Structure Nucleosides = Sugar + Base

7. Sugar Adenine Guanine Cytosine Thymine Purines Pyrimidines 1. DEOXYRIBONUCLEIC ACID (DNA) 1.1 Primary Structure Deoxyribose Nucleic acid bases

8. 1. DEOXYRIBONUCLEIC ACID (DNA) 1.1 Primary Structure Adenine (A) Cytosine (C) Guanine (G) Thymine (T) Note: Sugar phosphate backbone is constant Bases attached in apparently random order

9. o 10A G C A T T A T A G C Major G C groove T A T A T A Minor A T groove A T o A T 34A C G G C T A T A G C G C G C T A A T C G T A T A DNA DOUBLE HELIX 1. DEOXYRIBONUCLEIC ACID (DNA) 1.2 Secondary Structure - Double Helix • 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

10. o 10A G C A T T A T A G C Major G C groove T A T A T A Minor A T groove A T o A T 34A C G G C T A T A G C G C G C T A A T C G T A T A DNA DOUBLE HELIX 1. DEOXYRIBONUCLEIC ACID (DNA) 1.2 Secondary Structure - Double Helix Base Pairing G-C base pairing involves 3 H-bonds A-T base pairing involves 2 H-bonds

11. New DNA chains Template New Template DNA chains Replication DNA Daughter helices 1. DEOXYRIBONUCLEIC ACID (DNA) 1.2 Secondary Structure - Double Helix DNA Double Helix

12. Trinucleotide Template Template Template 5' X 5' 5' chain chain chain A A A A - X C C C X T A T T A 3' C G 3' C G C G 3' G C G C G C 3' 5' 3' 5' 3' 5' Growing Growing Growing chain chain chain Approach of trinucleotide Base pairing Enzyme catalysed 'splicing' 1. DEOXYRIBONUCLEIC ACID (DNA) 1.2 Secondary Structure - Double Helix

13. 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

14. Ribose Uracil 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

15. 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

16. 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

17. Yeast alanine-tRNA mI Methylinosine I Inosine UH2 Dihydrouridine T Ribothymidine Ps Pseudouridine mG Methylguanosine m2G Dimethylguanosine 2. RIBONUCLEIC ACID (RNA) 3'p end 2.3 Tertiary structure 5'p end Anticodon - the 3 bases are specific for the attached amino acid - base pair to the complementary triplet code on m- RNA (the codon)

18. mRNA mRNA A A C C A T A G A G G A A G G G T T A G T A A C C A G A C C A A C C C A A C C A A C C C A C C C C C A C U U U U G G G G G G T T T T G T G T T T U U U U U U U U T T T T Transcription DNA unravelled to reveal gene 2. RIBONUCLEIC ACID (RNA) 2.4 Transcription The copying of a segment of DNA which codes for a specific protein DNA double helix

19. Growing protein chain His GCA Ribosome 60S P-site A-site GCU CGA CAU GUC mRNA 40S 2. RIBONUCLEIC ACID (RNA) 2.5 Translation - protein synthesis

20. Protein chain transferred His GCA Ribosome 60S P-site A-site CGA CAU GUC mRNA 40S 2. RIBONUCLEIC ACID (RNA) 2.5 Translation - protein synthesis OH GCU

21. Protein chain transferred His OH GCA Ribosome 60S GCU P-site A-site CGA CAU GUC mRNA 40S 2. RIBONUCLEIC ACID (RNA) 2.5 Translation - protein synthesis

22. Protein chain transferred His GCA Ribosome 60S P-site A-site CGA CAU GUC mRNA 40S 2. RIBONUCLEIC ACID (RNA) 2.5 Translation - protein synthesis

23. Protein chain transferred His Val tRNA CAG GCA Ribosome 60S P-site A-site CGA CAU GUC mRNA 40S 2. RIBONUCLEIC ACID (RNA) 2.5 Translation - protein synthesis Translocation

24. Transfer of growing peptide chain to next amino acid 2. RIBONUCLEIC ACID (RNA) 2.5 Translation - protein synthesis

25. mRNA Ribosome Translation Transcription Nucleus 2. RIBONUCLEIC ACID (RNA) 2.5 Translation - protein synthesis Overview mRNA