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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN:

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 2: Section 10.2. Contents Part 2: Sections 10.2 3. Pharmacophore 3.1. Structural (2D) Pharmacophore (7 slides) 3.2. 3D Pharmacophore (6 slides)

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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN:

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  1. Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 2: Section 10.2

  2. Contents Part 2: Sections 10.2 3. Pharmacophore 3.1. Structural (2D) Pharmacophore (7 slides) 3.2. 3D Pharmacophore (6 slides) 3.3. Generalised Bonding Type Pharmacophore 3.4. The Active Conformation 3.5. Pharmacophores from Target Binding Sites 3.6. Pharmacophoric Triangles [20 slides]

  3. DRUG DESIGN AND DEVELOPMENT Stages 1) Identify target disease 2) Identify drug target 3) Establish testing procedures 4) Find a lead compound 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials

  4. 3. PHARMACOPHORE • Defines the important groups involved in binding • Defines the relative positions of the binding groups • Need to know Active Conformation • Important to Drug Design • Important to Drug Discovery

  5. 3.1 Structural (2D) Pharmacophore Defines minimum skeleton connecting important binding groups

  6. HO MORPHINE O NMe HO

  7. IMPORTANT GROUPS FOR ANALGESIC ACTIVITY HO MORPHINE O NMe HO

  8. IMPORTANT GROUPS FOR ANALGESIC ACTIVITY HO MORPHINE O NMe HO

  9. ANALGESIC PHARMACOPHORE FOR OPIATES HO N

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

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

  12. 3.2 3D Pharmacophore Defines relative positions in space of important binding groups Example

  13. IMPORTANT GROUPS FOR ACTIVITY HO MORPHINE O NMe HO

  14. HO O NMe HO

  15. O Ar N

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

  17. 3.3 Generalised Bonding Type Pharmacophore Defines relative positions in space of the binding interactions which are required for activity / binding

  18. Locked bonds 3.4 The Active Conformation • Need to identify the active conformation in order to identify the 3D pharmacophore • Conformational analysis - identifies possible conformations and their activities • Conformational analysis is difficult for simple flexible molecules with large numbers of conformations • Compare activity 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 3.5 Pharmacophores from Target Binding Sites

  20. 3.6 Pharmacophoric Triangles Pharmacophore triangles for dopamine

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