1. DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS
Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 10
DRUG DESIGN:
OPTIMIZING TARGET INTERACTIONS
Part 3: Sections –

2. Contents
Part 3: Sections –
4. Drug Design - Optimising Binding Interactions
4.1. Vary Alkyl Substituents (20 slides)
4.2. Vary Aryl Substituents (3 slides)
4.3. Extension - Extra Functional Groups (2 slides)
4.4. Chain Extension / Contraction (2 slides)
4.5. Ring Expansion / Contraction (2 slides)
4.6. Ring Variations (4 slides)
4.7. Isosteres and Bio-isosteres (3 slides)
[39 slides]

3. DRUG DESIGN AND 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

4. 4. DRUG DESIGN - OPTIMISING BINDING INTERACTIONS
AIM - To optimise binding interactions with target
REASONS
To increase activity and reduce dose levels
To increase selectivity and reduce side effects
STRATEGIES
Vary alkyl substituents
Vary aryl substituents
Extension
Chain extensions / contractions
Ring expansions / contractions
Ring variation
Isosteres
Simplification
Rigidification

5. 4.1 Vary Alkyl Substituents
Rationale :
Alkyl group in lead compound may interact with hydrophobic
region in binding site
Vary length and bulk of group to optimise interaction

6. 4.1 Vary Alkyl Substituents
Rationale :
Vary length and bulk of alkyl group to introduce selectivity
Binding region for N
Receptor 1
Receptor 2

7. 4.1 Vary Alkyl Substituents
Rationale:
Vary length and bulk of alkyl group to introduce selectivity
Example:
Selectivity of adrenergic agonists and antagonists for b-adrenoceptors over a-adrenoceptors

8. 4.1 Vary Alkyl Substituents
Adrenaline
Salbutamol
(Ventolin)
(Anti-asthmatic)
Propranolol
(b-Blocker)

9. a-Adrenoceptor H-Bonding region Ionic bonding Van der Waals

10. a-Adrenoceptor
ADRENALINE

11. a-Adrenoceptor

12. b-Adrenoceptor
ADRENALINE

13. b-Adrenoceptor
SALBUTAMOL

14. b-Adrenoceptor

15. a-Adrenoceptor
SALBUTAMOL

16. a-Adrenoceptor
SALBUTAMOL

17. a-Adrenoceptor
SALBUTAMOL

18. a-Adrenoceptor
SALBUTAMOL

19. a-Adrenoceptor
SALBUTAMOL

20. a-Adrenoceptor
SALBUTAMOL

21. a-Adrenoceptor
SALBUTAMOL

22. a-Adrenoceptor

23. 4.1 Vary Alkyl Substituents
Notes on synthetic feasibility of analogues
Feasible to remove alkyl substituents on heteroatoms
and replace with other alkyl substituents
Difficult to modify alkyl substituents on the carbon skeleton of a lead compound. Full synthesis is usually required

24. 4.1 Vary Alkyl Substituents
Methods

25. 4.2 Vary Aryl Substituents
Vary substituents
Vary substitution pattern
Weak
H-Bond
Binding Region
(H-Bond)
(for Y)
Strong
H-Bond
(increased
activity)

26. 4.2 Vary Aryl Substituents
Vary substitution pattern to enhance binding interactions
Benzopyrans
Anti-arrhythmic activity best when substituent is at 7-position

27. 4.2 Vary Aryl Substituents
Vary substitution pattern to enhance binding strength indirectly
- electronic effects
Binding strength of NH2 as HBD affected by relative position of NO2
Stronger when NO2 is at para position

28. 4.3 Extension - Extra Functional Groups
Rationale : To explore target binding site for further binding
regions to achieve additional binding interactions
RECEPTOR
RECEPTOR
Extra
functional
group
Unused
binding
region
DRUG
DRUG
Drug
Extension
Binding regions
Binding group

29. 4.3 Extension - Extra Functional Groups
Example : ACE Inhibitors
Hydrophobic pocket
Vacant
EXTENSION
Hydrophobic pocket
Binding
site
Binding
site

30. 4.4 Chain Extension / Contraction
Rationale :
Useful if a chain is present connecting two binding groups
Vary length of chain to optimise interactions
Weak
interaction
Strong
interaction A B
Chain
extension A B
RECEPTOR
RECEPTOR
Binding regions
Binding groups
A & B

31. 4.4 Chain Extension / Contraction
Example : N-Phenethylmorphine
Binding
group
Optimum chain length = 2

32. 4.5 Ring Expansion / Contraction
Rationale : To improve overlap of binding groups with their binding regions R
Ring
expansion R
Hydrophobic regions

33. 4.5 Ring Expansion / Contraction
Vary n
to vary
ring size
Example
Binding regions
Binding site
Binding site

34. 4.6 Ring Variations Rationale :
Replace aromatic/heterocyclic rings with other ring systems
Often done for patent reasons
General structure
for NSAIDS
Core
scaffold

35. 4.6 Ring Variations Rationale : Example :
Sometimes results in improved properties
Example :
Ring
variation
Antifungal agent
Improved selectivity
vs. fungal enzyme

36. 4.6 Ring Variations Example - Nevirapine (antiviral agent) Additional
binding group

37. 4.6 Ring Variations Example - Pronethalol (b-blocker) Selective for
b-receptors
over a-receptors

38. 4.7 Isosteres and Bio-isosteres
Rationale (isosteres) :
Replace a functional group with a group of same valency (isostere) e.g. OH replaced by SH, NH2, CH O replaced by S, NH, CH2
Leads to more controlled changes in steric/electronic properties
May affect binding and / or stability

39. 4.7 Isosteres and Bio-isosteres
Useful for SAR
Propranolol (b-blocker)
Replacing OCH2 with CH=CH, SCH2, CH2CH2
eliminates activity
Replacing OCH2 with NHCH2 retains activity
Implies O involved in binding (HBA)

40. 4.7 Isosteres and Bio-isosteres
Rationale (Bio-isosteres) :
Replace a functional group with another group which retains the same biological activity
Not necessarily the same valency
Example
antipsychotics
Pyrrole ring =
bio-isostere for
amide group
Improved selectivity
for D3 receptor
over D2 receptor