1. QSAR BY HANSCH ANALYSIS
Presented by – Vishal Singh Solanki
Guided by – Dr. A. Basu
2. CONTENT
Introduction
Graph and equation
Regression or correlation coefficient
Physicochemical properties
Application of qsar
Advantages
Disadvantages
Hansch equation
References
3. INTRODUCTION
The identification of a new drug molecule requires a lot of
synthesis, time and money. It was identified that out of billion
molecules synthesized, around one or two molecules reach the
clinical trials.
The quantitative structure activity relationship approach has
proved extremely useful in overcome this problem.
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.
4. Graphs and equations
• A range of compounds is synthesized in order to vary one
physicochemical property and to test how this affects the
biological activity. A graph is then plot the biological activity
0n the y-axis versus the physicochemical feature on x-axis.
5. The best line will be the closet to the data points . To measure how
close the data points vertical lines are drawn from each points. The
best line through the points will be the line where total is minimum.
Conti…
6. Regression or correlation coefficient
(r) :
It is measure of how well the equation explains the variance in
activity observed in terms of physicochemical parameters
present in the equation.
To illustrate ‘r’ following numerical data will be used.
There are 6 compounds in the study (n=6).
Yexp = log(observed activity)
X = physicochemical property
8. The QSAR equation derived from the data is:
log(activity)=Ycalc= k1 X + k2
= -0.47 – 0.002
The correlation coefficient r for the above equation
calculated using:
r2 = 1 – SScalc / SSmean
Where SScalc= measure how much the experimental activity
of compounds varies from calculated value.
SSmean= measure how much the experimental activity varies
from the mean of all experimental activities.
Conti…
9. If there is a correlation between the activity (Y) and the
parameter (X), the line of the equation should pass closer to
the data pts than representing mean.
It means:
SScalc < SSmean
According to data:
r2= 1 – 0.1912/ 0.5279
= o.638
This shows 64%
variability in activity
due to parameter X .
This should be less
than 80% so equation
is not good one.
For a perfect
correlation
calculated values for
activity =
experimental ones.
r2= 1
Conti…
10. a) Hydrophobicity Log P (partition coefficient)
LogP = [drug] in octanol / [drug] in water
Vary log P & see how this affects the biological activity.
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 concentration.
PHYSICOCHEMICAL PROPERTIES
11. Plot log 1/C vs. log P
Typically over a small range of log P, e.g. 1-4, a straight line
is obtained
log 1/C = k1 log P + k2
If graph is extended to very high log P values then get parabolic
curve. Reasons:
poorly soluble in aqueous phase
trapped in fat depots
more susceptible to metabolism
Conti…
12. Straight line
For parabolic curve
Log 1/C = -k (logp)2 + k2 logp + k3
The substituent hydrophobicity
constant()
x = logpx – logph
Where-
Ph= partition coefficient of std
compound
Px= partition coefficient for std with
substituent
13. • b) Steric Effect
• The bulk, size and shape of drug will influence how easily it
can approach and interact with binding site. A bulky
substituent may help to orientate a drug properly for
maximum binding n increase activity.
• Examples are:
Taft’s steric factor (Es) (~1956), the value for Es can be
obtained by comparing the rates of hydrolysis of substituted
aliphatic esters against a std ester under acidic conditions.
Es = logkx – logk0
Kx - represents rate of hydrolysis of an aliphatic ester having
substituent X
K0 - represent rate of hydrolysis of reference ester.
14. Verloop steric parameter
It involves a computer program called sterimol which
calculates steric substituent values from std bond angles,
van der waals radii, bond lengths n conformations
Example : L= length of substituent
B1-B4= radii of grp in different dimensions.
15. c) Electronic Effect
• Hammet substituent constant ()
This is a measure of the electron-withdrawing or
electron-donating ability of a substituent.
x = log(kx/kh)= logkx – logkh
kh dissociation constant (H signifies that there is no
substituents on aromatic ring).
16. Examples
COOH COO + H K0
COOH COO + H KpX X
COOH COO + H Km
X X
para = log10
meta = log10
Kp
Km
K0
K0
17. Electron withdrawing group, result in the aromatic ring
having a stronger and stabilizing influence on carboxylate
anion.
The equilibrium shift more to ionized form such n larger kx
value. (+ve value).
If substituent X is an electron donating group such as alkyl,
then aromatic ring less able to stabilize the carboxylate ion.
Equilibrium shifts to left n smaller kx value. ( -ve value)
Conti…
18. Application of QSAR
Diagnosis of MOA of drug.
Prediction of activity.
Prediction of toxicity.
Lead compound optimization.
Environmental chemistry.
19. Advantages
• Quantifying the relationship between structure and activity
provides an understanding of the effect of structure on activity.
• It is also possible to make predictions leading to synthesis of
novel analogues.
The results can be used to help understand interaction between
functional groups in the molecules of greatest activity with
those of their target
20. Disadvantages
False correlations because biological data that are
considerable experimental error.
If training dataset is not large enough , the data collected may
not reflect the complete property.
Features may not be reliable. This is particularly serious for 3D
features because 3D structures of ligands binding to receptor
may not available
21. HANSCH EQUATION
• In a simple situation where biological activity is related to
only one such property, a simple equation can be drawn up.
The biological activity of most drugs, however, is related to a
combination physicochemical properties. In such cases,
simple equations involving only one parameter are relevant
only if the other parameters are kept constant. In reality, this
is not easy to achieve and equations which relate biological
activity to a number of different parameters are known as
HANSCH EQUATION.
• They relate biological activity to the most commonly used
physicochemical properties (logp or , and a steric factor).
If the range of hydrophobicity values is limited then the
equation will be linear , as follows:
22. • Log(1/C) = k1 logP + k2 + k3 Es + k4
•
• If the logP values are spread over the large range, then the
equation will be parabolic:
• LogP= -k1 (logP)2 + K2 logP + k3 + k4 Es +k5
• (the constants k1-k5 are determined by computer software in
order to get best fitting equation)
HANSCH EQUATION
24. Merits of Hansch Analysis
•
1. Correlates activities with physicochemical parameters
2. “Outside” predictions are possible
25. Limitations of Hansch analysis
• 1. There must be parameter values available for the
substituent’s in the data set
• 2. A large number of compounds is required.
• 3. Depends on biological results (Chance of error)
• 4. Interrelationship of parameters
• 5. Groups should be selected in such a way that it should
contain at least one representative from each cluster.
• 6. Lead optimization technique, not a lead discovery
technique.
• 7. Risk of failure in “too far outside” predictions
26. conclusion
QSAR relate the physiological properties of a series of
drug to their biological activity by means of
mathematically equation.
27. REFERENCES
Patrick L. Graham “An introduction to medicinal chemistry’’ 4th edition by
Oxford University , New York
http://www.ccl.net/qsar/archives/0207/0029.html
http://www.srmuniv.ac.in/downloads/qsar.pdf&sa=u&ved