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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

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

MORPHINE

O

NMe

HO





HO

HO

O

NMe

HO

NMe

H3C

CH3

METAZOCINE

MORPHINE

HO

NMe

LEVORPHANOL


HO

HO

O

NMe

H3C

NMe

CH3

HO

METAZOCINE

MORPHINE

HO

NMe

LEVORPHANOL


3D pharmacophore

Defines relative positions in space of important binding groups

Example


Important groups for activity

HO

MORPHINE

O

NMe

HO


HO

O

NMe

HO


O

Ar

N


2.798 A

18.5o

150o

4.534 A

7.098 A

11.3o

O

Ar

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 derWaals interaction

Ionic interaction


2.798 A

18.5o

150o

4.534 A

7.098 A

11.3o

3D Pharmacophore

O

Ar

N


2.798 A

18.5o

150o

4.534 A

7.098 A

11.3o

Bonding type

pharmacophore

HBA

vdW

Ionic


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


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


Pharmacophoretriangles

Pharmacophore triangles for dopamine


Identifying the pharmacophore
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.