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Chapter 13 Part 2

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PharmacophorePharmacophore

• Defnes the important groups involved inbinding

• Defnes the relative positions o the bindinggroups

• Need to know the active con ormation

• mportant to drug design

• mportant to drug discover!

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Structural (2D) pharmacophoreStructural (2D) pharmacophore

Defnes minimum skeleton connecting important binding

groups

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O

NMe

HO

HO

MORPHINE

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O

N Me

HO

HO

MORPHINE

Important groups for analgesic activity

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O

N Me

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

N Me

HO

HO

N Me

HO

LEVORPHANOL

N Me

HO

METAZOCINE

CH3

H3C

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3D pharmacophore3D pharmacophore

De nes relative positions in space of important binding groups

!ample!ample

N

HO

HO

N

x

x

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O

N Me

HO

HO

MORPHINE

Important groups for activity

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O

N Me

HO

HO

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""

##

ArAr

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""

##

ArAr

11"3 o

1#$ o

1%"#o

&"$'% (

2"&'% (

)"#3) (

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Note*Note* Defnes relative positions in space o the important binding interactions

which are re+uired or activit!

,!drogen bonding acceptor,!drogen bonding donorvan der -aals interaction

onic interaction

$enerali%ed bonding type pharmacophore$enerali%ed bonding type pharmacophore

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""

##

ArAr

11"3 o

1#$ o

1%"#o

&"$'% (

2"&'% (

)"#3) (

3D Pharmacophore3D Pharmacophore

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&'A&'A

IonicIonic

vdvd

11"3 o

1#$ o

1%"#o

&"$'% (

2"&'% (

)"#3) (

'onding type'onding typepharmacophorepharmacophore

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HO N H2 H O

NH2

HO H OII IIII

HO N H2 H O

NH2

HO H O

he active conformationhe active conformation • .he con ormation adopted b! a drug when it binds to its target• dentifcation o the active con ormation is re+uired in order to identi !the 3D pharmacophore• Con ormational anal!sis identifes possible con ormations and theirstabilities• Con ormational anal!sis is di/cult or 0e ible molecules with largenumbers o con ormations• asier to compare activities o rigid analogues

*oc+ed bonds

N H 2H O

H O

Dopamine

,otatablebonds

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Pharmacophores from target binding sitesPharmacophores from target binding sites

H-bonddonor oracceptor

aromaticcenter

basic o rpositivecenter

H-bonddonor oracceptor

aromaticcenter

basic o rpositivecenter

Pharmacophore

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Pharmacophore trianglesPharmacophore triangles

HO

NH 2

HO

Pharmacophore triangles for dopamine

HO

NH 2

HO

HO

NH 2

HO

ArAr

Basic

HBD/HBA

HBD/HBA

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HN

O 2 N

OH

HN

S

CH 3

O HN

NEt 2

CH 3

Cl

N

N

H

H 3 C

A

amni+uine is an important .hird -orld

drug used in the treatment oschistosomiasis 4bilhar5ia6" Consider thestructures below o o amni+uine 4 A6 and twoo the additional drugs tested in the designo o amni+uine" 7ased on these structures8draw the pharmacophore o o amni+uine"