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

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

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

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

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

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

9. 1 © 1. DEOXYRIBONUCLEIC ACID (DNA) Sugar phosphate backbone is ionised and faces outward (favourable interactions with water)Sugar phosphate backbone is ionised and faces outward (favourable interactions with water) Nucleic acid bases point inward and pair up A-T or G-CNucleic acid bases point inward and pair up A-T or G-C Purine pairs with pyrimidine - constant diameter to helixPurine pairs with pyrimidine - constant diameter to helix Base bairs are stacked (vdw interactions between pairs)Base bairs are stacked (vdw interactions between pairs) Chains are complementaryChains are complementary T o 34A o 10A DNA DOUBLE HELIX T A G C A T C GC TA AT CG A TA TA TA TA TA GC C TA TA A GC T CG CG AT AT Major groove Minor groove G G 1.2 Secondary Structure - Double Helix

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

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

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

13. 1 © 1. DEOXYRIBONUCLEIC ACID (DNA) 1.3 Tertiary Structure Double helix coils into a 3D shape - supercoilingDouble helix coils into a 3D shape - supercoiling Double helix has to unravel during replicationDouble helix has to unravel during replication Unravelling leads to strainUnravelling leads to strain Relieved by enzyme catalysed cutting and repair of DNA chainRelieved by enzyme catalysed cutting and repair of DNA chain Important to the activity of the quinolone and fluoroquinolone antibacterial agents which act as enzyme inhibitorsImportant to the activity of the quinolone and fluoroquinolone antibacterial agents which act as enzyme inhibitors

14. 1 © 2. RIBONUCLEIC ACID (RNA) 2.1 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 Uracil Ribose

15. 1 © 2. RIBONUCLEIC ACID (RNA) 2.2 Secondary structure Single strandedSingle stranded Some regions of helical secondary structure exist due to base pairing within the same strand (see t-RNA)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 cytosineAdenine pairs to uracil; guanine pairs to cytosine

16. 1 © 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 production site Transfer RNA (tRNA)Transfer RNA (tRNA) The adapter unit linking the triplet code on mRNA to specific amino acids Ribosomal RNA (rRNA)Ribosomal RNA (rRNA) Present in ribosomes (the production site for protein synthesis). Important both structurally and catalytically 2.3 Tertiary structure

17. 1 © mI Methylinosine I Inosine UH2 Dihydrouridine T Ribothymidine Ps Pseudouridine mG Methylguanosine m2G Dimethylguanosine 2. RIBONUCLEIC ACID (RNA) 2.3 Tertiary structure Anticodon - the 3 bases are specific for the attached amino acid - base pair to the complementary triplet code on m- RNA (the codon) Yeast alanine-tRNA 3'p end 5'p end

18. 1 © 2. RIBONUCLEIC ACID (RNA) 2.4 Transcription The copying of a segment of DNA which codes for a specific protein DNA double helix DNA unravelled to reveal gene A G A T A C C A G G G A A T T C T A T G G T C C C T T A Transcription mRNA A G A T A C C A G G G A A T U C U A U G G U C C C U U A T C T A T G G T C C C T T A mRNA U C U A U G G U C C C U U A

19. 1 © 2. RIBONUCLEIC ACID (RNA) Ribosome 60S 40S A-site P-site mRNA CGA CAU GUC 2.5 Translation - protein synthesis Growing protein chain GCU GCAHis

20. 1 © 2. RIBONUCLEIC ACID (RNA) Ribosome 60S 40S A-site P-site mRNA CGA CAU GUC 2.5 Translation - protein synthesis Protein chain transferredGCU GCAHisOH

21. 1 © 2. RIBONUCLEIC ACID (RNA) Ribosome 60S 40S A-site P-site mRNA CGA CAU GUC 2.5 Translation - protein synthesis Protein chain transferred GCAHis GCUOH

22. 1 © 2. RIBONUCLEIC ACID (RNA) Ribosome 60S 40S A-site P-site mRNA CGA CAU GUC 2.5 Translation - protein synthesis Protein chain transferred GCAHis

23. 1 © 2. RIBONUCLEIC ACID (RNA) Ribosome 60S 40S A-site P-site mRNA CGA CAU GUC 2.5 Translation - protein synthesis Protein chain transferred GCAHis CAGValtRNA Translocation

24. 1 © 2. RIBONUCLEIC ACID (RNA) 2.5 Translation - protein synthesis Transfer of growing peptide chain to next amino acid

25. 1 © Nucleus 2. RIBONUCLEIC ACID (RNA) Transcription mRNA Translation 2.5 Translation - protein synthesis Overview Ribosome