1. DR. MANJOOR AHAMAD SYED,
M.Pharm,Ph.D
Assist. Professor
Department of Medicinal Chemistry,
College of Public Health and Medical Sciences,
Mettu University, Mettu
Post Box No-318
Ethiopia.
QSAR
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5. QSAR approach attempts to identify and quantify the physicochemical properties
of a drug and to see whether any of these properties has an effect on the drug’s
biological activity by using a mathematical equation
PHYSICOCHEMICAL PROPERTIES
•Hydrophobicity of the molecule
•Hydrophobicity of substituents
•Electronic properties of substituents
•Steric properties of substituents
QSAR
6. A range of compounds is synthesized in order to vary one
physicochemical property and to test it affects the bioactivity.
A graph is then drawn to plot the biological activity on the
y axis versus the physicochemical feature on the x axis.
It is necessary to draw the best possible line through the
data points on the graph. This done by procedure known as
linear regression analysis by the least square method.
7. Log (1/C)
Log P
. .. . .
.
..
.
0.78 3.82
If we draw a line through a set of data points will be
scattered on either side of the line. The best line will be the
one closest to the data points.
To measure how close the data points are , vertical lines
are drawn from each point.
14. 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
0.98 1.97 2.3
(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
23. ELECTRONIC EFFECT
The electronic effect of various sustituents will clearly have
an effect on drug ionisation and polarity.
Have an effect on how easily a drug can pass through the cell
membrane or how strongly it can interact with a binding site.
Hammet substituent constant(σ) this is a measure of electron
with-drawing or electron-donating ability of a substituents on an
aromatic ring.
24. COOH COO
-
+
H
+
KH = Dissociation constant =
[PhCO ]
[PhCO 2H]
2
-
σ for aromatic substituents is measured by comparing the
dissociation constants of substituted benzoic acids with
benzoic acid
25. X= electron withdrawing group (e.g. NO2,)
+
X = electron
withdrawing
group
X
CO2
CO H
2
X
H
Charge is stabilised by X
Equilibrium shifts to right
KX > KH
σ X = log
K X
K H
= logK X - logK H
Positive value
26. X= electron donating group (e.g. CH3)
σ X = log
K X
K H
= logK X - logK H
Charge destabilised
Equilibrium shifts to left
KX < KH
Negative value
COOH COO
-
+ H
+
X X
27.
28. Log
1
C
1.22 - 1.59 + 7.89
Conclusions:
• Activity increases if is +ve (i.e. hydrophobic substituents)
• Activity increases if is negative (i.e. e-donating substituents)
Example: Adrenergic blocking activity of -halo--arylamines
CH CH2 NRR'
X
Y
29. STERIC FACTORS
The bulk, size and shape of a drug will influence how easily it can approach and
interact with binding site. It is a measure of the bulkiness of the group
It represents and it effects on the closeness of contact between the drug and receptor
site.
Bulky substituent may help to orient a drug property for maximum binding and
increase activity.
A bulky substituents may act like a shield and hinder the ideal interaction between a
drug and its binding site.
Bulky substituent may help to orient a drug properly for
maximum binding and increase activity.
30. Taft’s Steric Factor (Es)
It is measure by the comparing the rate of hydrolysis of substituted
aliphatic esters against a standard ester under acidic condition
31. Disadvantages
ES value measures intramolecular steric effect but drugs interact with target binding site in
intermolecular process (i.e. a drug binding to a receptor)
32. Minimal Steric Difference
MSD assesses the difference between the molecules in terms of the parts
that do not overlap when one chemical formula is placed on top of the
other.
Example:
Pepperdine have one –CH2 group extra when compared with pyrrolidine.
The extra –CH2 group measures MSD, since this is the only portion that
does not overlap.
33.
34. Molar Refractivity (MR)
this is a measure of a substituent’s volume
MR =
(n2
- 1)
(n2
- 2)
x
mol. wt.
density
Correction factor
for polarisation
(n=index of
refraction)
Defines volume
This is perticularly significant if the substituent has π
electrons or lone pair of electrons
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48. Pharmacophore Modeling
A pharmacophore is the ensemble of steric and
electronic features that is necessary to ensure
the optimal molecular interactions with a specific
biological target and to trigger (or block) its
biological response
49.
50. Pharmacophore Features
• HB Acceptor & HB Donor
• Hydrophobic
• Hydrophobic aliphatic
• Hydrophobic aromatic
• Positive charge/Pos. Ionizable
• Negative charge/Neg. Ionizable
• Ring Aromatic
Each feature consists of four parts:
1. Chemical function
2. Location and orientation in 3D space
3. Tolerance in location
4. Weight
51.
52.
53. Pharmacophoric Features
H bond Acceptor H bond Acceptor-Lipophilic H bond Donor
Ring aromatic
Positively Ionizable
Negatively Ionizable Positive Charge
Negative Charge
Hydrophobic
Hydrophobic-
Aliphatic
Hydrophobic-
Aromatic
55. 24
PHARMACOPHORE SELECTION
+
C O 2 H
C H 3
H
H
L
NPHD
DN
d 1
d 2 d 3
+
H
HO
L
CH3
N
PH
D
d 1
d 2 d 3
L
P D
d1
d2
D
d3
PHARMACOPHORE
ODH
L-LIPOPHILIC SITE
D-H- BOND DONOR
PD-PROTONATED H-
BOND DONOR
57. Name of the drug discovered Biol. Activity
1. Erythromycin analogs Antibacterial
2. New sulfonamide dervs. Antibacterial
3. Rifampicin dervs. Anti-t.B.
4. Napthoquinones antimalerials
5. Mitomycins antileukemia
6. Pyridine –2-methanol’s spasmolytics
7. Cyclopropalamines MAO inhibitors
8. -Carbolines MAO inhibitors
9. Phenyl oxazolidines radioprotectives
10.Hydantoin dervs. Anti cns-tumors
11.Quinolones antibacterial
Drug Design Successes (Fruits of QSAR)
58.
59. REFERENCES
1. An introduction to medicinal chemistry by Graham L Patric
3rd edition pagee no:271-298
2. Foye : Principles of medicinal chemistry
3. Burgers medicinal chemistry
