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Simplification Strategies in Drug Design

Learn about the rationale, methods, advantages, and disadvantages of simplifying lead compounds in drug design to optimize target interactions. Examples and risks of oversimplification are discussed with relevant case studies.

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Simplification Strategies in Drug Design

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  1. Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 4: Section 10.3.8

  2. Contents Part 4: Section 10.3.8 4.8. Simplification - Rationale - Methods (9 slides) - Example (2 slides) - Disadvantages (14 slides) - Example of oversimplification (8 slides) [36 slides]

  3. 4.8 Simplification • Rationale : • Lead compounds from natural sources are often complex and difficult to synthesise • Simplifying the molecule makes synthesis of analogues easier, quicker and cheaper • Simpler structures may fit binding site easier and increase activity • Simpler structures may be more selective and less toxic if excess functional groups removed

  4. 4.8 Simplification • Methods: • Retain pharmacophore • Remove unnecessary functional groups

  5. Example Excess ring Excess functional groups 4.8 Simplification • Methods: • Remove excess rings

  6. 4.8 Simplification • Methods: • Remove asymmetric centres

  7. Pharmacophore 4.8 Simplification • Methods: • Simplify in stages to avoid oversimplification • Simplification does not mean ‘pruning groups’ off the lead • compound • Compounds usually made by total synthesis

  8. Pharmacophore 4.8 Simplification Example • Important binding groups retained • Unnecessary ester removed • Complex ring system removed

  9. 4.8 Simplification Example Devazepide Excess rings removed Asperlicin - CCK antagonist Possible lead for treating panic attacks

  10. 4.8 Simplification • Disadvantages: • Oversimplification may result in decreased activity and selectivity • Simpler molecules have more conformations • More likely to interact with more than one target binding site.

  11. Target binding site

  12. Target binding site

  13. Rotatable bonds Target binding site

  14. Rotatable bonds Target binding site

  15. Rotatable bonds Target binding site

  16. Rotatable bonds Target binding site

  17. Rotatable bonds Target binding site

  18. Rotatable bonds Target binding site

  19. Rotatable bonds Target binding site

  20. Rotatable bonds Target binding site

  21. Rotatable bonds Target binding site

  22. Rotatable bonds Target binding site

  23. Rotatable bonds Target binding site

  24. Rotatable bonds Different binding site - side effects

  25. 4.8 Simplification • Example of oversimplification • Simplification of opiates

  26. MORPHINE C C O C C C C N SIMPLIFICATION

  27. LEVORPHANOL C C O C C C C N SIMPLIFICATION

  28. LEVORPHANOL C C O C C C C N SIMPLIFICATION

  29. METAZOCINE C C O C C C C N SIMPLIFICATION

  30. C C O C C C C N OVERSIMPLIFICATION

  31. TYRAMINE C C O C C C C N OVERSIMPLIFICATION

  32. AMPHETAMINE C C O C C C C N OVERSIMPLIFICATION

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