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Page 1: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

Chapter 13 Part 2

Page 2: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

PharmacophorePharmacophore

• 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

Page 3: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

Structural (2D) pharmacophoreStructural (2D) pharmacophore

Defines minimum skeleton connecting important binding groups

Page 4: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

O

NMe

HO

HO

MORPHINE

Page 5: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

O

NMe

HO

HO

MORPHINE

Important groups for analgesic activity

Page 6: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

O

NMe

HO

HO

MORPHINE

Important groups for analgesic activity

Page 7: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

N

HO

Analgesic pharmacophore for opioids

Page 8: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

MORPHINE

O

NMe

HO

HO

NMe

HO

LEVORPHANOL

NMe

HO

METAZOCINE

CH3

H3C

Page 9: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

MORPHINE

O

NMe

HO

HO

NMe

HO

LEVORPHANOL

NMe

HO

METAZOCINE

CH3

H3C

Page 10: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

3D pharmacophore3D pharmacophore

Defines relative positions in space of important binding groups

ExampleExample

N

HO

HO

N

x

x

Page 11: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

O

NMe

HO

HO

MORPHINE

Important groups for activity

Page 12: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

O

NMe

HO

HO

Page 13: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the
Page 14: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

OO

NN

ArAr

Page 15: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

OO

NN

ArAr

11.3o

150o

18.5o

7.098 A

2.798 A

4.534 A

Page 16: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

Note:Note: Defines relative positions in space of the important binding interactions which are required for activity

Hydrogen bonding acceptorHydrogen bonding donorvan der Waals interactionIonic interaction

Generalized bonding type pharmacophoreGeneralized bonding type pharmacophore

Page 17: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

OO

NN

ArAr

11.3o

150o

18.5o

7.098 A

2.798 A

4.534 A

3D Pharmacophore3D Pharmacophore

Page 18: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

HBAHBA

IonicIonic

vdWvdW

11.3o

150o

18.5o

7.098 A

2.798 A

4.534 A

Bonding typeBonding typepharmacophorepharmacophore

Page 19: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

HO NH2 HO

NH2

HO HO

II IIII

HO NH2 HO

NH2

HO HO

The active conformationThe 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

Locked bonds

NH2HO

HO

Dopamine

Rotatable bonds

Page 20: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

Pharmacophores from target binding sitesPharmacophores from target binding sites

H-bonddonor oracceptor

aromaticcenter

basic orpositive center

H-bonddonor oracceptor

aromaticcenter

basic orpositive center

Pharmacophore

Page 21: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

Pharmacophore trianglesPharmacophore triangles

HO

NH2

HO

Pharmacophore triangles for dopamine

HO

NH2

HO

HO

NH2

HO

ArAr

Basic

HBD/HBA

HBD/HBA

Page 22: Chapter 13 Part 2. Pharmacophore Defines the important groups involved in binding Defines the relative positions of the binding groups Need to know the

HN

O2N

OH

HN

S

CH3

O HNNEt2

CH3

Cl

N

N

H

H3C

A

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.


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