chapter 13 part 2. pharmacophore defines the important groups involved in binding defines the...
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Chapter 13 Part 2
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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
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Structural (2D) pharmacophoreStructural (2D) pharmacophore
Defines minimum skeleton connecting important binding groups
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O
NMe
HO
HO
MORPHINE
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O
NMe
HO
HO
MORPHINE
Important groups for analgesic activity
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O
NMe
HO
HO
MORPHINE
Important groups for analgesic activity
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N
HO
Analgesic pharmacophore for opioids
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MORPHINE
O
NMe
HO
HO
NMe
HO
LEVORPHANOL
NMe
HO
METAZOCINE
CH3
H3C
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MORPHINE
O
NMe
HO
HO
NMe
HO
LEVORPHANOL
NMe
HO
METAZOCINE
CH3
H3C
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3D pharmacophore3D pharmacophore
Defines relative positions in space of important binding groups
ExampleExample
N
HO
HO
N
x
x
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O
NMe
HO
HO
MORPHINE
Important groups for activity
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O
NMe
HO
HO
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OO
NN
ArAr
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OO
NN
ArAr
11.3o
150o
18.5o
7.098 A
2.798 A
4.534 A
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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
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OO
NN
ArAr
11.3o
150o
18.5o
7.098 A
2.798 A
4.534 A
3D Pharmacophore3D Pharmacophore
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HBAHBA
IonicIonic
vdWvdW
11.3o
150o
18.5o
7.098 A
2.798 A
4.534 A
Bonding typeBonding typepharmacophorepharmacophore
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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
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Pharmacophores from target binding sitesPharmacophores from target binding sites
H-bonddonor oracceptor
aromaticcenter
basic orpositive center
H-bonddonor oracceptor
aromaticcenter
basic orpositive center
Pharmacophore
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Pharmacophore trianglesPharmacophore triangles
HO
NH2
HO
Pharmacophore triangles for dopamine
HO
NH2
HO
HO
NH2
HO
ArAr
Basic
HBD/HBA
HBD/HBA
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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.