1. Several methods are presently used to study SAR.
5- Structure-Activity Relationships (SAR).
A structure-activity relationship (SAR) is a statement of the effect of structure change on biological activity within a congeneric series (a family) of compounds.
Methods of Studying Structure-Activity Relationships.
Both the affinity of a drug for its receptor and its intrinsic activity are determined by its chemical structure.
Several methods are presently used to study SAR.

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 testing in vitro - tests for binding interactions with target in 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

3. 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

4. 6. Identification of the active part:
Only a small part of the lead compound may be involved in the appropriate receptor interactions. The relevant groups on a molecule that interact with a receptor and are responsible for the activity are collectively known as the pharmacophore. The other atoms in the lead molecule, referred to as auxophore.

5. PHARMACOPHORE Defines the important groups involved in binding
Defines the relative positions of the binding groups
Need to know Active Conformation
Important to Drug Design
Important to Drug Discovery

6. Auxophore There are three types of auxophore:
Essential to maintain the integrity of the molecule and hold the pharmacophoric groups in their appropriate positions.
Interfere with the binding of the pharmacophore to the receptor and need to be removed from the lead compound

7. Some atoms of the auxophore may be dangling in the space within the receptor and are neither binding to the receptor nor preventing the pharmacophoric atoms from binding. [these atoms can be modified without loss of potency]. Also it can be modified to solve pharmacokinetic problems [absorption, distribution, metabolism, and excretion]

8. Pharmacophoric descriptors are including :
Pharmacophore
It is that portion of the molecule containing the essential organic functional groups that directly interact with the receptor active site and therefore confers upon the molecule the biologic activity of interest.
Pharmacophoric descriptors are including :
 H-bond sites
Hydrophobic and electrostatic interaction sites
Ring centers and virtual points
 Distances, 3D relationship

9. Sulphonamides pharmacophore sulfanilamide sulfamethoxazole
sulfadiazine
sulfisoxazole
Sulphonamides
p-aminobenzoic acid
pharmacophore

10. Quinolones & fluoroquinolones
ciprofloxacin
ofloxacin
moxifloxacin
nalidixic acid

11. L = lipophilic site; A = H-bond acceptor;
Pharmacophore
Dopamine
L = lipophilic site; A = H-bond acceptor;
D = H-bond donor; PD = protonated H-bond donor

13. Identification of the active part ( Pharmacophore)
Simplification of the original lead compound is especially appropriate for polycyclic natural substances.
In this process, systemic synthesis and evaluation of simpler analogues of the lead molecule is performed.
Simplification of cocaine molecule led to introduction of many local anaesthetic drugs and discovery of benzoic acid ester moiety as a pharmacophore for such activity.
The main result of this methodology is the identification of the pharmacophore group.

14. 6.1 Structural (2D) Pharmacophore
Defines minimum skeleton connecting important binding groups HO O
NMe HO

15. HO O
MORPHINE
NMe
MOR025.WAV HO

16. HO O MORPHINE NMe HO IMPORTANT GROUPS FOR ANALGESIC ACTIVITY
MOR025.WAV HO

17. ANALGESIC PHARMACOPHORE FOR OPIATES
MOR025.WAV

18. HO HO O H3C NMe NMe CH3 METAZOCINE MORPHINE HO NMe LEVORPHANOL
MOR025.WAV
NMe
LEVORPHANOL

19. HO HO O H3C NMe NMe CH3 HO METAZOCINE MORPHINE HO NMe LEVORPHANOL
MOR025.WAV
NMe
LEVORPHANOL

20. D Pharmacophore
Defines relative positions in space of important binding groups
Example

21. O
NMe HO
MOR028.WAV

22. MOR028.WAV

23. O N Ar
MOR028.WAV

24. O N Ar
11.3o
150o
18.5o
7.098 A
2.798 A
4.534 A
MOR028.WAV

25. 6.3 The Active Conformation
Need to identify the active conformation in order to identify the 3D pharmacophore
Conformational analysis - identifies possible conformations and their activities
Conformational analysis is difficult for simple flexible molecules with large numbers of conformations
Compare activity of rigid analogues
Locked bonds

26. 6.4 Pharmacophores from Target Binding Sites2 A S P
SER
PHE
Binding
site
H-bond
donor or
acceptor
aromatic
center
basic or
positive
H-bond
donor or
acceptor
basic or
positive
center
Pharmacophore
aromatic
center

27. QSAR is mathematical relationships linking chemical structure and pharmacological activity in a quantitative manner for a series of compounds. Methods which can be used in QSAR include various regression and pattern recognition techniques.

28. Adrenergic blocking activity of b-halo-b-arylamines
Examples:
Adrenergic blocking activity of b-halo-b-arylamines
Log 1 C æ è ö ø =
1.22 p -
1.59 s +
7.89
Conclusions:
Activity increases if p is + (i.e. hydrophobic substituents)
Activity increases if s is negative (i.e. e-donating substituents)

29. 7. 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
The approaches for molecular modification can be classified as:
I. General approach
II. Special approach

30. I. General approach
1- Molecular disjunction (molecular dissociation, dissection or simplification)

31. 2- Molecular conjunctive approaches
Association of two or more molecules to give more complex analogues of the lead molecules with improved pharmacokinetic and pharmacodynamic properties represents typical process of conjunctive strategy.
Molecular association processes comprise :-
Molecular addition
Molecular replication
Molecular hybridization

32. a. Molecular addition
Molecular addition involves association of different molecules through weak forces such electrostatic attraction or hydrogen bonding.
e.g. Electrostatic attraction in the urinary antiseptic
methenamine mandelate.

33. b. Molecular replication
Molecular replication involves association of identical molecules through covalent bond formation (identical twin drug).

34. c. Molecular hybridization
Molecular hybridization involves association of two different molecules through covalent bond formation ( non identical twin drug).

35. 35

36. II. Special approach 1. Variation of alkyl substituents.
2. Extention of the structure.
3. Ring closure or ring opening
4. Ring expansion and ring contraction
5. Homologation and chain branching
6. Introduction of unsaturation center
7. Introduction, removal or replacement of bulky
groups
8. Introduction of chiral center
9. Conformation restriction (molecular rigidification)
10. Isosteres and bioisosteres

37. 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

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

39. 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

40. 1. Vary Alkyl Substituents
Adrenaline
Salbutamol
(Ventolin)
(Anti-asthmatic)
Propranolol
(b-Blocker)

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

42. a-Adrenoceptor
ADRENALINE

43. a-Adrenoceptor

44. b-Adrenoceptor
ADRENALINE

45. b-Adrenoceptor
SALBUTAMOL

46. b-Adrenoceptor

47. a-Adrenoceptor
SALBUTAMOL

48. a-Adrenoceptor
SALBUTAMOL

49. a-Adrenoceptor
SALBUTAMOL

50. a-Adrenoceptor
SALBUTAMOL

51. a-Adrenoceptor
SALBUTAMOL

52. a-Adrenoceptor
SALBUTAMOL

53. a-Adrenoceptor
SALBUTAMOL

54. a-Adrenoceptor

55. 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

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

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

58. 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

59. 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

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

61. Extension - extra functional groups
Example: Second-generation anti-impotence drugs
Viagra
Notes:
Extension - addition of pyridine ring
Increased target selectivity

62. 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

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

64. 4- Homologation A homologous series is a group of compounds that
differ by a constant unit, generally a CH2 group

65. e.g., alkyltrimethylammonium analogs possess different types of activity depending on the length of alkyl group:
n= muscarinic agonists
n= 6 or partial agonists
n= 8 or more muscarinic antagonists.
A homologous series is a series of analogs that differ in structure by simple increment in molecular formula.
These may produced by sequential chemical changes which includes increasing or decreasing the length of a carbon chain.

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

67. 5. Ring Expansion / Contraction
Vary n
to vary
ring size
Example
Binding regions
Binding site
Binding site

68. Ring Enlargement and Ring Contraction:

69. 6 . Ring Variations Rationale :
Replace aromatic/heterocyclic rings with other ring systems
Often done for patent reasons
General structure
for NSAIDS
Core
scaffold

70. 6 . Ring Variations Rationale : Example :
Sometimes results in improved properties
Example :
Ring
variation
Antifungal agent
Improved selectivity
vs. fungal enzyme

71. 6. Ring Variations Example - Nevirapine (antiviral agent) Additional
binding group

72. 7-Introduction, removal or replacement of bulky groups
This special process is used mainly to:
Convert agonist to antagonist or
Prevent the enzymatic degradation
This process is mainly used to convert agonist to antagonist and vice versa.
Acetyl choline can cause muscle contraction
Propantheline cause muscle relaxation
Isopreterenol is non selective beta agonist used to treat bradycardia
Prpranolol is non selective beta antagonist used to treat hypertension

73. Example for preventing enzymatic degradation;
β-lactamase resistant penicillins
Bulky group introduced near the ring prevent enzymatic degradation by …..
Methicillin

74. Introduction, Removal, or Replacement of Bulky groups:

75. 8. Ring Closure and Opening :

76. 9- Introduction of chiral centers
Receptors are chiral entities and the interactions of many drugs at specific sites are chirality type of interaction.
E.g. The simple addition of α-methyl group to give ACE inhibitor captopril increased by 10-folds over the des-methyl compound.