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Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS Part 1: Section 10.1 (SAR). Contents Part 1: Section 10.1 (SAR) 1.Introduction to drug design & development 2.Structure Activity Relationships (SAR) (2 slides)

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Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Patrick

An Introduction to Medicinal Chemistry 3/e

Chapter 10

DRUG DESIGN:

OPTIMIZING TARGET INTERACTIONS

Part 1: Section 10.1 (SAR)


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Contents

Part 1: Section 10.1 (SAR)

1.Introduction to drug design & development

2.Structure Activity Relationships (SAR) (2 slides)

2.1.SAR on Alcohols (2 slides)

2.2.SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N) (4 slides)

2.3.SAR on Quaternary Ammonium Salts (R4N+)

2.4.SAR on Aldehydes and Ketones (2 slides)

2.5.SAR on Esters (2 slides)

2.6.SAR on Amides (3 slides)

2.7.SAR on Carboxylic Acids (3 slides)

2.8.SAR on Aromatic Rings and Alkenes (2 slides)

2.9.Miscellaneous Functional Groups in Drugs

2.10. SAR of Alkyl Groups (2 slides)

[26 slides]


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

1. Introduction to drug design & development

Stages

1) Identify target disease

2) Identify drug target

3) Establish testing procedures

4) Find a lead compound

5) Structure Activity Relationships (SAR)

6) Identify a pharmacophore

7) Drug design- optimising target interactions

8) Drug design - optimising pharmacokinetic properties

9) Toxicological and safety tests

10) Chemical development and production

11) Patenting and regulatory affairs

12) Clinical trials


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

2. Structure Activity Relationships (SAR)

AIM - Identify which functional groups are important for binding

and/or activity

METHOD

  • Alter, remove or mask a functional group

  • Test the analogue for activity

  • Conclusions depend on the method of testingin vitro - tests for binding interactions with targetin vivo - tests for target binding interactions and/or pharmacokinetics

  • If in vitro activity drops, it implies group is important for binding

  • If in vivo activity unaffected, it implies group is not important


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

2. Structure Activity Relationships (SAR)

NOTES ON ANALOGUES

  • Modifications may disrupt binding by electronic / steric effects

  • Easiest analogues to make are those made from lead compound

  • Possible modifications may depend on other groups present

  • Some analogues may have to be made by a full synthesis(e.g. replacing an aromatic ring with a cyclohexane ring)

  • Allows identification of important groups involved in binding

  • Allows identification of the pharmacophore


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

HBD

HBA

Drug

Drug

H

O

O

H

X

X

H

X= N or O

Binding site

Binding site

Ether

Ester

Alkane

2.1 SAR on Alcohols

Possible binding interactions

Possible analogues


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

CH3

CH3

O

O

H

X

X

X= N or O

Ether analogue

Ether analogue

steric shield

Binding site

Binding site

2.1 SAR on Alcohols

Possible effect of analogues on binding

(e.g. ether)

No interaction as HBD

No interaction as HBA


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

HBD

Drug

Drug

NH2R

+

+

X

X= N or O

CO2-

Binding site

Binding site

+

H

R3NH acts as a

strong HBD

N

R2

2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)

Possible binding interactions if amine is ionised

Ionic

H-Bonding


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

HBD

HBA

Drug

Drug

H

N

N

H

X

X

R

X= N or O

Binding site

Binding site

R

H

2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)

Possible binding interactions for free base

H-Bonding

Note:

3o Amines are only able to act as HBA’s - no hydrogen available to act as HBD


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

CO2-

Binding site

O

Amide

analogue

N

CH3

R

  • 1o and 2o amines are converted to 2o and 3o amides respectively

  • Amides cannot ionise and so ionic bonding is not possible

  • An amide N is a poor HBA and so this eliminates HBA interactions

  • Steric effect of acyl group is likely to hinder NH acting as a HBD (2o amide)

No interaction

2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)

Analogues of

1o & 2o amines

Effect on binding


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)

Analogues of 3o amines containing a methyl substituent


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Ionic

bonding

Induced

dipole

interactions

d+

+

+

d-

CO2-

Binding site

Binding site

Drug

Drug

NR3

NR3

2.3 SAR on Quaternary Ammonium Salts (R4N+)

Possible binding interactions

Analogues

Full synthesis of 1o-3o amines and amides


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Dipole-dipole

interaction

H-Bonding

HBA

Drug

Drug

O

O

H

X

Binding site (X= N or O)

Binding site

2.4 SAR on Aldehydes and Ketones

Possible binding interactions

Analogues


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Alcohol

analogue

H

H

Binding site (X= N or O)

X

OH

2.4 SAR on Aldehydes and Ketones

Effect on binding

Change in stereochemistry (planar to tetrahedral)

May move oxygen out of range

If still active, further reactions can be carried out on

alcohol to establish importance of oxygen


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

2.5 SAR on Esters

Possible binding interactions

H-bonding as HBA by either oxygen

Analogues

  • Hydrolysis splits molecule and may lead to a loss of activity due to loss of other functional groups - only suitable for simple esters.

  • Hydrolysis leads to a dramatic increase in polarity which may influence ability of analogue to reach target if in vivo tests are used

  • Reduction to alcohol removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction can be difficult to do if other labile functional groups are present


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Ester masking polar groups

allowing passage through

fatty cell membranes

2.5 SAR on Esters

  • Esters are usually hydrolysed by esterases in the blood

  • Esters are more likely to be important for pharmacokinetic reasons i.e. acting as prodrugs


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Drug

H

N

O

HBD

HBA

R

H

X

Binding site (X= N or O)

Binding site (X= N or O)

O

Drug

R

N

H

X

2.6 SAR on Amides

Possible binding interactions

  • The nitrogen of an amide cannot act as a HBA - lone pair interacts with neighbouring carbonyl group

  • Tertiary amides unable to act as HBD’s


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

2.6 SAR on Amides

Analogues

  • Hydrolysis splits molecule and may lead to loss of activity due to loss of other functional groups - only suitable for simple amides.

  • Hydrolysis leads to dramatic increase in polarity which may affect ability of analogue to reach target if in vivo tests are done

  • Reduction to amine removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction may be difficult to do if other labile groups are present


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

O

R

N

CH3

H

Analogue

X

Analogue

No binding as HBD

Binding of O as HBA hindered

steric shield

O

R

N

CH3

binding site

X

2.6 SAR on Amides

Analogues

  • N-Methylation prevents HBD interaction and may introduce a steric effect that prevents an HBA interaction


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Drug

O

Drug

C

HBA

HBD

HBA

O

H

O

C

H

H

H

O

X

X

Binding site (X= N or O)

Binding site (X= N or O)

Binding site (X= N or O)

Drug

O

C

X

O

H

2.7 SAR on Carboxylic Acids

Possible binding interactions as free acid


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Drug

Drug

O

O

HBA

Ionic bonding

C

C

+

O

O

H

X

Binding site (X= N or O)

Binding site (X= N or O)

-

-

NHR2

2.7 SAR on Carboxylic Acids

Possible binding interactions as carboxylate ion

  • Charged oxygen atoms are strong HBA’s

  • Group could interact both as an ion and as a HBA at the same time


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

+

H

X

No ionic bonding possible

H-Bonding hindered

Analogue

Analogue

NHR2

O

O

C

C

steric shield

O

O

CH3

CH3

binding site

2.7 SAR on Carboxylic Acids

Possible analogues

  • Possible effects

  • Reduction removes carbonyl oxygen as potential HBA and prevents ionisation

  • Esterification prevents ionisation, HBD interactions and may hinder HBA by a steric effect


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Drug

Drug

R

R

vdw

binding site

binding site

vdw

hydrophobic

region

hydrophobic

pocket

2.8 SAR on Aromatic Rings and Alkenes

Possible binding interactions

Possible analogues


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Analogue

Analogue

binding site

binding site

‘Buffers’

R

hydrophobic

region

R

hydrophobic

pocket

H

H

H

H

2.8 SAR on Aromatic Rings and Alkenes

Possible effects on binding

No

fit


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

2.9 Miscellaneous Functional Groups in Drugs

  • Acid chlorides - too reactive to be of use

  • Acid anhydrides- too reactive to be of use

  • Alkyl halides-present in anticancer drugs to form covalent bonds with nucleophiles in target

  • Aryl halides -commonly present. Not usually involved in binding directly

  • Nitro groups -sometimes present but often toxic

  • Alkynes -sometimes present, but not usually important in binding interactions

  • Thiols -present in some drugs as important binding group to transition metals (e.g. Zn in zinc metalloproteinases)

  • Nitriles - present in some drugs but rarely involved in binding

  • Functional groups may be important for electronic reasons (e.g. nitro, cyano, aryl halides)

  • Functional groups may be important for steric reasons

    • (e.g. alkynes)


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Drug

Drug

van der Waals

interactions

binding site

binding site

CH3

H3C

CH3

hydrophobic ‘pocket’

hydrophobic slot

CH3

2.10 SAR of Alkyl Groups

Possible interactions


Patrick an introduction to medicinal chemistry 3 e chapter 10 drug design

Drug

Drug

Drug

Analogue

Analogue

Analogue

2.10 SAR of Alkyl Groups

  • Analogues

  • Easiest alkyl groups to vary are substituents on heteroatoms

  • Vary length and bulk of alkyl group to test space available


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