Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN:

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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal

ChemistryChemistry 3/e 3/e

Chapter 10Chapter 10

DRUG DESIGN: DRUG DESIGN: OPTIMIZING TARGET OPTIMIZING TARGET

INTERACTIONSINTERACTIONS

Part 2: Section 10.2Part 2: Section 10.2

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ContentsContents

Part 2: Sections 10.2

3. Pharmacophore3.1. Structural (2D) Pharmacophore (7 slides)3.2. 3D Pharmacophore (6 slides)3.3. Generalised Bonding Type Pharmacophore3.4. The Active Conformation 3.5. Pharmacophores from Target Binding Sites 3.6. Pharmacophoric Triangles

[20 slides]

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DRUG DESIGN AND DEVELOPMENTDRUG DESIGN AND DEVELOPMENT

StagesStages

1) Identify target disease1) Identify target disease 2) Identify drug target2) Identify drug target 3) Establish testing procedures3) Establish testing procedures 4) Find a lead compound4) Find a lead compound 5) Structure Activity Relationships (SAR)5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore6) Identify a pharmacophore 7) Drug design- optimising target interactions7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests9) Toxicological and safety tests10) Chemical development and production10) Chemical development and production11) Patenting and regulatory affairs11) Patenting and regulatory affairs12) Clinical trials12) Clinical trials

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3. PHARMACOPHORE3. PHARMACOPHORE

• Defines the important groups involved in bindingDefines the important groups involved in binding

• Defines the relative positions of the binding groupsDefines the relative positions of the binding groups

• Need to know Active ConformationNeed to know Active Conformation

• Important to Drug DesignImportant to Drug Design

• Important to Drug DiscoveryImportant to Drug Discovery

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3.1 Structural (2D) Pharmacophore3.1 Structural (2D) Pharmacophore

Defines minimum skeleton connecting important binding groups 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 ACTIVITYIMPORTANT GROUPS FOR ANALGESIC ACTIVITY

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O

NMe

HO

HO

MORPHINE

IMPORTANT GROUPS FOR ANALGESIC ACTIVITYIMPORTANT GROUPS FOR ANALGESIC ACTIVITY

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N

HO

ANALGESIC PHARMACOPHORE FOR OPIATESANALGESIC PHARMACOPHORE FOR OPIATES

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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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3.2 3D Pharmacophore3.2 3D Pharmacophore

Defines relative positions in space of important binding groups 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 ACTIVITYIMPORTANT 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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Defines relative positions in space of the binding interactions Defines relative positions in space of the binding interactions which are required for activity / bindingwhich are required for activity / binding

3.3 Generalised Bonding Type Pharmacophore3.3 Generalised Bonding Type Pharmacophore

Ar

Ar

x

x

y

BaseHBA

HBDHBA Base

HBA

HBDHBA

y

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3.4 The Active Conformation3.4 The Active Conformation

• Need to identify the active conformation in order to identify the Need to identify the active conformation in order to identify the 3D pharmacophore 3D pharmacophore

• Conformational analysis - identifies possible conformations and Conformational analysis - identifies possible conformations and their activities their activities

• Conformational analysis is difficult for simple flexible Conformational analysis is difficult for simple flexible molecules with large numbers of conformationsmolecules with large numbers of conformations

• Compare activity of rigid analoguesCompare activity of rigid analogues

NH2HO HO NH2 HO

NH2

HO HO HO

I II

rotatable bonds

Dopamine

Locked bondsLocked bonds

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3.5 Pharmacophores from Target Binding Sites3.5 Pharmacophores from Target Binding Sites

H-bonddonor oracceptor

aromaticcenter

basic orpositive center

H-bonddonor oracceptor

aromaticcenter

basic orpositive center

Pharmacophore

OH

CO2

ASP

SER

PHE

Bindingsite

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3.6 Pharmacophoric Triangles3.6 Pharmacophoric Triangles

HO

NH2

HO

Pharmacophore triangles for dopaminePharmacophore triangles for dopamine

HO

NH2

HO

HO

NH2

HO

ArAr

Basic

HBD/HBA

HBD/HBA