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Pharmacophores

Pharmacophores. Chapter 13 Part 2. Pharmacophore. Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the active conformation Important to drug design Important to drug discovery. Structural (2D) pharmacophore.

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Pharmacophores

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  1. Pharmacophores Chapter 13 Part 2

  2. Pharmacophore • Defines the important groups involved in binding • Defines the relative positions of the binding groups • Need to know the active conformation • Important to drug design • Important to drug discovery

  3. Structural (2D) pharmacophore Defines minimum skeleton connecting important binding groups

  4. HO MORPHINE O NMe HO

  5. Important groups for analgesic activity HO MORPHINE O NMe HO

  6. Important groups for analgesic activity HO MORPHINE O NMe HO

  7. Analgesic pharmacophore for opioids HO N

  8. HO HO O NMe HO NMe H3C CH3 METAZOCINE MORPHINE HO NMe LEVORPHANOL

  9. HO HO O NMe H3C NMe CH3 HO METAZOCINE MORPHINE HO NMe LEVORPHANOL

  10. 3D pharmacophore Defines relative positions in space of important binding groups Example

  11. Important groups for activity HO MORPHINE O NMe HO

  12. HO O NMe HO

  13. O Ar N

  14. 2.798 A 18.5o 150o 4.534 A 7.098 A 11.3o O Ar N

  15. Generalized bonding type pharmacophore Note: Defines relative positions in space of the important binding interactions which are required for activity Hydrogen bonding acceptor Hydrogen bonding donor van derWaals interaction Ionic interaction

  16. 2.798 A 18.5o 150o 4.534 A 7.098 A 11.3o 3D Pharmacophore O Ar N

  17. 2.798 A 18.5o 150o 4.534 A 7.098 A 11.3o Bonding type pharmacophore HBA vdW Ionic

  18. Rotatable bonds I II Dopamine Locked bonds The active conformation • The conformation adopted by a drug when it binds to its target • Identification of the active conformation is required in order to identify the 3D pharmacophore • Conformational analysis identifies possible conformations and their stabilities • Conformational analysis is difficult for flexible molecules with large numbers of conformations • Easier to compare activities of rigid analogues

  19. SER H-bond Binding O A S P donor or site H basic or acceptor positive C O 2 center H-bond basic or donor or positive acceptor center aromatic center aromatic center Pharmacophore PHE Pharmacophoresfrom target binding sites

  20. Pharmacophoretriangles Pharmacophore triangles for dopamine

  21. Identifying the pharmacophore • Oxamniquine is an important Third World drug used in the treatment of schistosomiasis (bilharzia). Consider the structures below of oxamniquine (A) and two of the additional drugs tested in the design of oxamniquine. Based on these structures, draw the pharmacophore of oxamniquine.

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