Pharmacophores Chapter 13 Part 2.

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Presentation transcript:

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 Defines minimum skeleton connecting important binding groups

HO O MORPHINE NMe MOR025.WAV HO

HO O MORPHINE NMe HO Important groups for analgesic activity MOR025.WAV HO

HO O MORPHINE NMe HO Important groups for analgesic activity MOR025.WAV HO

Analgesic pharmacophore for opioids MOR025.WAV

HO HO O H3C NMe NMe CH3 METAZOCINE MORPHINE HO NMe LEVORPHANOL MOR025.WAV NMe LEVORPHANOL

HO HO O H3C NMe NMe CH3 HO METAZOCINE MORPHINE HO NMe LEVORPHANOL MOR025.WAV NMe LEVORPHANOL

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

Important groups for activity HO O MORPHINE NMe MOR025.WAV HO

HO O NMe MOR028.WAV HO

MOR028.WAV

O N Ar MOR028.WAV

O 7.098 A 2.798 A 4.534 A 11.3o 150o 18.5o Ar MOR028.WAV N

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 der Waals interaction Ionic interaction

3D Pharmacophore O 2.798 A Ar 4.534 A 7.098 A MOR028.WAV N 18.5o 150o

Bonding type pharmacophore 2.798 A HBA vdW 4.534 A 7.098 A MOR028.WAV Ionic

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 Rotatable bonds I II Dopamine Locked bonds

Pharmacophores from target binding sites 2 A S P SER PHE Binding site H-bond donor or acceptor aromatic center basic or positive H-bond donor or acceptor basic or positive center Pharmacophore aromatic center

Pharmacophore triangles Pharmacophore triangles for dopamine

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.