1. Structure Activity Relationships (SAR) And
Quantitative Structure Activity Relationships (QSAR)
Sachin Shinde
S.M.Joshi College ,Hadapsar,Pune

2. What is SAR
It is intended to give the relationship between chemical structure of a molecule and its biological activity.
The analysis of SAR enables the determination of the chemical groups responsible for biological effect
How is it carried out
This involves synthesis and testing of all analogues for biological activity and comparing them with the original compound.
If an analogue shows a significant lower activity, then the group that has been modified must be important.
If the activity remains unchanged, then the group is not essential.

3. Lead developement
Once the structure of lead compound is known, the medicinal chemist moves on to study its SAR.
The aim is to discover which parts of the molecule are important to biological activity (Pharmacophore) and which are not.
SAR is synthesizing compounds, where one particular functional group of the molecule is removed or altered.
In this way it is possible to find out which groups are essential and which are not for biological effect.

4. Identification of Pharmacophore by chopping the molecule

7. The binding role of double bonds

9. Bioisosterism for creating new analogues
Bioisosteres - substituents or groups with chemical or physical similarities that produce similar biological properties. Can attenuate toxicity, modify activity of lead, and/or alter pharmacokinetics of lead.

10. Classical Isosteres

11. Non-Classical Isosteres
Do not have the same number of atoms and do not fit steric and electronic rules of classical isosteres, but have similar biological activity.

12. Drug analogs can also be made by
I) Changing the size and shape of the lead molecule
- number of methylene groups in chains and rings
- increasing or decreasing the degree of unsaturation
introducing or removing a ring system
Changing the stereochemistry
II) Introduction of a new substituent

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23. Introduction of new substituents
Methyl groups
Paracetamol
Reduced hepatotoxicity

24. Solubility and membrane permeability
Adding polar groups
Adding polar groups increases polarity and decreases hydrophobic character
Useful for targeting drugs vs. gut infections
Useful for reducing CNS side effects
Antifungal agent with poor
solubility - skin infections only
Systemic antifungal agent
improved blood solubility
Disadvantage:
May introduce unwanted side effects

25. Drug stability Metabolic blockers Rationale:
Metabolism of drugs usually occur at specific sites. Introduce groups at a susceptible site to block the reaction
Increases metabolic stability and drug lifetime
Oral contraceptive
- limited lifetime

26. Drug Designing using Quantitative Structure- Activity Relationships (QSAR)

27. What is QSAR?
QSAR is a mathematical relationship between biological activity of a molecular system and its geometric and chemical characteristics.
QSAR attempts to find consistent relationship between biological activity and molecular properties, so that these “rules” can be used to evaluate the activity of new compounds.

28. Estimation of the concentration of given solution
O.D
O.D
Concentration mg/ml
concentration
y = mx+c

29. Introduction to QSAR Aims
To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula
Requirements
Quantitative measurements for biological and physicochemical properties
Physicochemical Properties
Hydrophobicity of the molecule
Hydrophobicity of substituents
Electronic properties of substituents
Steric properties of substituents
Most common
properties studied

31. ADME

32. Intermolecular binding forces
Electrostatic or ionic bond
Hydrogen Bonds
Binding site
Hydrophobic regions
Transient dipole on drug d+ d-
van der Waals interaction
DRUG d+ d- d- d+
Van der Waals Interactions

33. Structured water layer round hydrophobic regions
Ion-dipole interactions d+ d- R C O d+ d- R C O
Binding site
Binding site
Hydrophobic interactions
Binding site
Drug
DRUG
Binding
Binding site
Drug
DRUG
Hydrophobic
regions
Water
Unstructured water
Increase in entropy
Structured water layer
round hydrophobic regions

34. There are two important aspects in drug design and drug strategies to improve :
Pharmacodynamics properties: to optimize the interaction of the drug with its target.
Pharmacokinetics properties: to improve the drug's ability to reach its target & to have acceptable lifetime.
Pharmacodynamics and pharmacokinetics should have equal priority in influencing which strategies are used and which analogues are synthesized.

35. New compounds with improved biological activity
QSAR and Drug Design
Compounds + biological activity
QSAR
New compounds with improved biological activity

36. Example of a QSAR
Anti-adrenergic Activity and Physicochemical Properties
of 3,4- disubstituted N,N-dimethyl-a-bromophenethylamines
p = Lipophilicity parameter
s = Hammett Sigma+ (for benzylic cations)
Es(meta) = Taft’s steric parameter

37. Example of a QSAR...
m-X p-Y p s Es(meta) log (1/C)obs log (1/C)a log (1/C)b
H H
F H
H F
Cl H
Cl F
Br H
I H
Me H
Br F
H Cl
Me F
H Br
Cl Cl
Br Cl
Me Cl
Cl Br
Me Br
H I
H Me
Me Me
Br Br
Br Me
Calc.
Calc.

38. Example of a QSAR... QSAR Equation a: (using 2 variables)
log (1/C) = p s
(n = 22; r = 0.945)
QSAR Equation b: (using 3 variables)
log (1/C) = p s Es(meta)
(n = 22; r = 0.959)

39. Hydrophobicity of the Molecule
Partition Coefficient P =
[Drug
in octanol]
[Drug in water]
High P
High hydrophobicity

40. Hydrophobicity of the Molecule
Example 2 General anaesthetic activity of ethers
(parabolic curve - larger range of log P values)
Log P o
Log (1/C)
Log 1 C æ è ö ø = -
0.22(logP) 2 +
1.04 logP
2.16
Optimum value of log P for anaesthetic activity = log Po
log 1/C = - k1 (log P) k2 log P + k3
Biological activity normally expressed as 1/C, where C = [drug] required to achieve a defined level of biological activity. The more active drugs require lower concentrations.

41. Log P Values: Uses
With these equations for anesthetics (ethers only), it is possible to predict activity if log P known (doesn’t work if structure very different)
ether chloroform halothane
(anesthetic activity increases in same order)
Drugs with Log P values close to 2 should be able to enter the CNS efficiently
e.g. barbiturates have log P values close to 2 also; want to make sure log P value is much lower if you don’t want possible CNS side effects

42. Hydrophobicity of Substituents
- the substituent hydrophobicity constant (p)
π = log PX – log PH
Benzene
(Log P
= 2.13)
Chlorobenzene
= 2.84)
Benzamide
= 0.64) C l O N H 2
Example :
pCl = 0.71
pCONH = -1.49 2
Positive values imply substituents are more hydrophobic than H
Negative values imply substituents are less
hydrophobic than H

43. p values for various substituents on aromatic rings
CH3
t-Bu OH
CONH2
CF3 Cl Br F
0.52
1.68
-0.67
-1.49
1.16
0.71
0.86
0.14
Theoretical Log P for chlorobenzene
= log P for benzene + p for Cl
= = 2.84
Theoretical Log P for meta-chlorobenzamide
= log P for benzene + p for Cl + p for CONH2
= = 1.35

44. Electronic Effects: The Hammett Constant s
Measure e-withdrawing or e-donating effects (compared to benzoic acid & how affected its ionization)

45. Hammett Substituent Constant (s)
X= electron withdrawing group (e.g. NO2)
Charge is stabilised by X
Equilibrium shifts to right
KX > KH s X =
log K H
logK -
Positive value

46. Hammett Substituent Constant ( s)
X= electron donating group (e.g. CH3)
Charge destabilised
Equilibrium shifts to left
KX < KH s X =
log K H
logK -
Negative value

47. Hammett Substituent Constant (s)
EXAMPLES:
sp (NO2) = 0.78
sm (NO2) = 0.71
meta-Substitution
e-withdrawing (inductive effect only)
para-Substitution
e-withdrawing
(inductive +
resonance effects)

48. Hammett Substituent Constant (s)
EXAMPLES:
sm (OH) = 0.12
sp (OH) = -0.37
meta-Substitution
e-withdrawing (inductive effect only)
para-Substitution
e-donating by resonance
more important than
inductive effect

49. Hammett Substituent Constant (s)
QSAR Equation:
Log (1/C) = s – 0.348
Diethylphenylphosphates
(Insecticides)
Conclusion : e-withdrawing substituents increase activity

50. Steric Effects
Examples are:
·        Taft’s steric factor (Es) (~1956), an experimental value based on Ester hydrolysis rate constants
·        Molar refractivity (MR)--measure of the volume occupied by an atom or group--equation includes the MW, density, and the index of refraction--
·        Verloop steric parameter--computer program uses bond angles, van der Waals radii, bond lengths

51. Steric Factors Taft’s Steric Factor (Es)
Measured by comparing the rates of hydrolysis of substituted aliphatic esters against a standard ester under acidic conditions
Es = log kx - log ko kx represents the rate of hydrolysis of a substituted ester
ko represents the rate of hydrolysis of the parent ester
Limited to substituents which interact sterically with the tetrahedral transition state for the reaction
Cannot be used for substituents which interact with the transition state by resonance or hydrogen bonding
May undervalue the steric effect of groups in an intermolecular process (i.e. a drug binding to a receptor)

52. Steric Factors MR = (n - 1) 2) x mol. wt. density
Molar Refractivity (MR) - a measure of a substituent’s volume MR = (n 2 - 1) 2) x
mol. wt.
density
Correction factor
for polarisation
(n=index of
refraction)
Defines volume

53. Steric Factors Verloop Steric Parameter
- calculated by software (STERIMOL)
- gives dimensions of a substituent
- can be used for any substituent L B 3 4 B4 B3 B2 B1
Example - Carboxylic acid

54. Hansch Equation
Example:Antimalarial activity of phenanthrene aminocarbinols
Log 1 C æ è ö ø = -
0.015 (logP) 2 +
0.14 logP
0.27 S p X
0.40 Y
0.65 s
0.88
2.34
Conclusions:
Activity increases slightly as log P (hydrophobicity) increases (note that the constant is only 0.14)
Parabolic equation implies an optimum log Po value for activity
Activity increases for hydrophobic substituents (esp. ring Y)
Activity increases for e-withdrawing substituents (esp. ring Y)

55. Craig Plots Plots of one parameter against another.
For example, p vs. s
Used to quickly decide which analogs to synthesize if the Hansch equation is known.
Allows an easy identification of suitable substituents for a QSAR analysis which includes both relevant properties

56. Craig Plot
Allows an easy identification of suitable substituents for a QSAR analysis which includes both relevant properties
Choose a substituent from each quadrant to ensure orthogonality
Choose substituents with a range of values for each property

57. Craig Plot
Craig plot shows values for 2 different physicochemical properties for various substituents -p +p
Example:
-s +p
+s +p
-s -p
+s -p

58. Topliss Scheme:
A noncomputerised, nonmathematical & nonstatistical method
Used to decide which substituents to use if optimising compounds
one by one (where synthesis is complex and slow and bioassays are easy & fast)
Example: Aromatic substituents
+s +p
-s -p
+s +p
-s +p
-s +p
-s +p

60. Topliss Scheme Rationale
Rationale
Replace H with
para-Cl (+p and +s)
Act.
Little
change
Act.
+p and/or +s
advantageous
favourable p
unfavourable s
+p and/or +s
disadvantageous
add second Cl to
increase p and s
further
replace with Me
(+p and -s)
replace with OMe
(-p and -s)
Further changes suggested based on arguments of p, s and
steric strain

61. Thank You