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2. DRUG TARGETS

2. DRUG TARGETS. 0. TARGET SELECTIVITY. Between species Antibacterial and antiviral agents Identify targets which are unique to the invading pathogen Identify targets which are shared but which are significantly different in structure Within the body

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2. DRUG TARGETS

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  1. 2. DRUG TARGETS 0 TARGET SELECTIVITY • Between species • Antibacterial and antiviral agents • Identify targets which are unique to the invading pathogen • Identify targets which are shared but which are significantly different in structure • Within the body • Selectivity between different enzymes, receptors etc. • Selectivity between receptor types and subtypes • Selectivity between isozymes • Organ selectivity

  2. 3.2.2 Testing with Receptors 0 • Not easy to isolate membrane bound receptors • Carried out on whole cells, tissue cultures, or isolated organs • Affinity - strength with which compounds bind to a receptor • Efficacy - measure of maximum biochemical effect resulting from binding of a compound to a receptor. • Potency - concentration of an agonist required to produce 50% of the maximum possible effect.

  3. 4.3 Lead Compounds from the Natural World 0 PLANT EXTRACTS • OPIUM- Morphine • CINCHONA BARK- Quinine • YEW TREE- Taxol

  4. 4.3 Lead Compounds from the Natural World 0 PLANT EXTRACTS WILLOW TREE - SALICYLIC ACID Aspirin COCA BUSH - COCAINE Procaine

  5. 4.3 Lead Compounds from the Natural World 0 VENOMS AND TOXINS Teprotide Captopril (anti-hypertensive)

  6. Agonist Agonist 4.3 Lead Compounds from the Natural World 0 ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS

  7. Antagonist Antagonist 4.3 Lead Compounds from the Natural World 0 ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS

  8. 4.4 Lead Compounds from the Synthetic World 0 PRONTOSIL

  9. 4.4 Lead Compounds from the Synthetic World 0 SULFANILAMIDE

  10. 4.4 Lead Compounds from the Synthetic World 0 TNT

  11. 4.4 Lead Compounds from the Synthetic World 0 RUBBER INDUSTRY ANTABUSE

  12. 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS AUTOMATED SYNTHETIC MACHINES

  13. AMINO ACID RESIN BEAD AMINO ACIDS X PEPTIDE 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - PEPTIDE SYNTHESIS

  14. Y CHR1R2 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS RESIN BEAD N N O

  15. R2 R3 H RESIN BEAD 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS N N O

  16. R2 R3 R4 R5 RESIN BEAD 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS N N O EtO O

  17. R2 R3 R4 R5 RESIN BEAD 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS N N N HN O

  18. Y R2 R3 R4 R5 4.4 Lead Compounds from the Synthetic World 0 COMBINATORIAL SYNTHESIS - HETEROCYCLIC SYNTHESIS RESIN BEAD N N N HN O

  19. Targets Lead compounds 4.5 Lead Compounds - Impact of the human genome project 0 The Past Lead Compound The Future Targets

  20. 4.6 Lead Compounds - de novo design 0

  21. 4.6 Lead Compounds - de novo design X-RAY CRYSTALLOGRAPHY

  22. 4.6 Lead Compounds - de novo design PROTEIN STRUCTURE

  23. 4.6 Lead Compounds - de novo design Receptor

  24. Scaffold CH3 + O Scaffold H3N Scaffold Scaffold Scaffold HO H-BOND CO2- IONIC BOND VDW BOND

  25. HN NH N O O O S N N N O S O N O H2N 4.6 Lead Compounds - de novo design THYMIDYLATE KINASE INHIBITOR LEAD COMPOUND Optimisation ANTICANCER AGENT

  26. 4.7 Design of Lead Compounds using NMR Spectroscopy 0 NMR SPECTROSCOPY

  27. 4.7 Design of Lead Compounds using NMR Spectroscopy 0 Binding Site Protein

  28. 4.7 Design of Lead Compounds using NMR Spectroscopy 0 Protein NO OBSERVABLE BIOLOGICAL EFFECT

  29. CH3 CH CH CH3 CH2 CH2 CH C C 4.7 Design of Lead Compounds using NMR Spectroscopy 0 13C NMR

  30. 4.7 Design of Lead Compounds using NMR Spectroscopy 0 CH3 CH CH CH3 CH2 CH2 CH C C 13C NMR

  31. 4.7 Design of Lead Compounds using NMR Spectroscopy 0 Protein Optimise epitope

  32. 4.7 Design of Lead Compounds using NMR Spectroscopy 0 Protein Optimise epitope Optimise epitope

  33. 4.7 Design of Lead Compounds using NMR Spectroscopy 0 Link Protein Optimise epitope Optimise epitope

  34. 4.7 Design of Lead Compounds using NMR Spectroscopy 0 LEAD COMPOUND

  35. Me 4.7 Design of Lead Compounds using NMR Spectroscopy 0 Design of a lead compound as an immunosuppressant Epitope B Epitope A

  36. Me 4.7 Design of Lead Compounds using NMR Spectroscopy 0 Design of a lead compound as an immunosuppressant Lead compound

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