Patrick: An Introduction to Medicinal Chemistry 6e Chapter 13 DRUG DESIGN PHARMACOPHORES modified

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

6. 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

6.1 Structural (2D) Pharmacophore Defines minimum skeleton connecting important binding groups

HO O MORPHINE NMe HO

IMPORTANT GROUPS FOR ANALGESIC ACTIVITY HO O MORPHINE NMe HO

IMPORTANT GROUPS FOR ANALGESIC ACTIVITY HO O MORPHINE NMe HO

ANALGESIC PHARMACOPHORE FOR OPIOIDS

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

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

6.2 3D Pharmacophore Defines relative positions in space of important binding groups Example Diagram refreshed

IMPORTANT GROUPS FOR ACTIVITY HO O MORPHINE NMe HO

HO O NMe HO

O N Ar

O 7.098 Å 2.798 Å 4.534 Å 11.3o 150o 18.5o Ar N

6.3 Generalised 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 der Waals interaction Ionic interaction

3D Pharmacophore O 7.098 Å 2.798 Å 4.534 Å 11.3o 150o 18.5o Ar N

Bonding type pharmacophore HBA 2.798 Å HBD 4.534 Å 7.098 Å Ionic HBD vdW 4.534 Å 7.098 Å Ionic HBD

6.4 The Active Conformation The conformation adopted by a drug when it binds to its target and produces the desired effect 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 Rotatable bonds I II Dopamine Locked bonds

6.5 Pharmacophores from Target Binding Sites 2 A S P SER PHE Binding site H-bond donor or acceptor Aromatic centre Basic or positive center H-bond donor or acceptor Basic or positive center Pharmacophore Aromatic centre modified Identify amino acid residues lining the target binding site Identify types of binding interactions that are possible to these residues Identify positions in which a suitable binding group should be placed to interact with amino acid residues Create a pharmacophore by linking up those positions

6.6 Pharmacophore Triangles Pharmacophore triangles for dopamine