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

1 © Contents Part 2: Sections 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]

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

1 © 3. PHARMACOPHORE Defines the important groups involved in bindingDefines the important groups involved in binding Defines the relative positions of the binding groupsDefines the relative positions of the binding groups Need to know Active ConformationNeed to know Active Conformation Important to Drug DesignImportant to Drug Design Important to Drug DiscoveryImportant to Drug Discovery

1 © 3.1 Structural (2D) Pharmacophore Defines minimum skeleton connecting important binding groups

1 © O NMe HO MORPHINE

1 © O NMe HO MORPHINE IMPORTANT GROUPS FOR ANALGESIC ACTIVITY

1 © O NMe HO MORPHINE IMPORTANT GROUPS FOR ANALGESIC ACTIVITY

1 © N HO ANALGESIC PHARMACOPHORE FOR OPIATES

1 © MORPHINE O NMe HO NMe HO LEVORPHANOL NMe HO METAZOCINE CH 3 H3CH3C

1 © MORPHINE O NMe HO NMe HO LEVORPHANOL NMe HO METAZOCINE CH 3 H3CH3C

1 © 3.2 3D Pharmacophore Defines relative positions in space of important binding groups Example

1 © O NMe HO MORPHINE IMPORTANT GROUPS FOR ACTIVITY

1 © O NMe HO

1 ©

1 © O N Ar

1 © O N Ar 11.3 o 150 o 18.5 o A A A

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

1 © 3.4 The Active Conformation Need to identify the active conformation in order to identify the 3D pharmacophoreNeed to identify the active conformation in order to identify the 3D pharmacophore Conformational analysis - identifies possible conformations and their activitiesConformational analysis - identifies possible conformations and their activities Conformational analysis is difficult for simple flexible molecules with large numbers of conformationsConformational analysis is difficult for simple flexible molecules with large numbers of conformations Compare activity of rigid analoguesCompare activity of rigid analogues Locked bonds

1 © 3.5 Pharmacophores from Target Binding Sites H-bond donor or acceptor aromatic center basic or positive center H-bond donor or acceptor aromatic center basic or positive center Pharmacophore O H CO 2 ASP SER PHE Binding site

1 © 3.6 Pharmacophoric Triangles Pharmacophore triangles for dopamine