Quantitative Structure-Activity Relationship (QSAR)

Quantitative structure activity relationship was firstly introduced by Corwin Hansch in 1960. It
is said to be a mathematical relationships in the form of an equation between the biological activity
and measurable physiochemical parameters. QSAR attempts to identify and quantify the
physiochemical properties of a drug and to see whether any of these property has an effect on drugs
biological activity. By quantifying physicochemical properties, it should be possible to calculate
in advance what the biological activity of a novel analogue might be. There are two advantages to
this. Firstly, it allows the medicinal chemist to target efforts on analogues which should have
improved activity and thus cut down the number of analogues which have to be made. Secondly,
if an analogue is discovered which does not fit the equation, it implies that some other feature is
important and provides a lead for further development The parameters used in QSAR is a measure
of the potential contribution of its group to a particular property of the parent drug.
Why QSAR is needed
QSAR is crucial in drug discovery. It helps in screening and designing compounds with desired
properties. It also help in saving time and resources in the drug development process or
environmental risk assessment. QSAR provides valuable insights into the relationship between
molecular structure and activity, aiding in the rational design of new compounds.
Software used
To obtain the functional relationship between data and method several software or tools are used,
such as Chemometrics, Chemoinformatics, MOE (Molecular operating environment), etc.
Graphs and equations
In the simplest situation, a range of compounds are synthesized in order to vary one
physicochemical property (e.g. log P) and to test
how this affects the biological activity (log 1/C)
(we will come to the meaning of log 1/C and log
P in due course). A graph is then drawn to plot
the biological activity on the y axis versus the
physico-chemical feature on the x axis.

y=𝑘1 𝑥 + 𝑘2
𝑘1 , 𝑘2 are constants, Y= dependent variable, x= independent variable

The significance of the equation is given by a term known as the regression coefficient (r) This
coefficient can again be calculated by computer. For a perfect fit, r2 = 1. Good fits generally have
r2 values of 0.95 or above.
Physiochemical Parameters
1 Hydrophobicity
Hydrophobicity of a drug is important parameter and may also be important in receptor interactions.
Changing substituents on a drug may well have significant effects on its hydrophobic character and hence
its biological activity. Therefore, it is important to have a means of predict ing this quantitatively. Play
major role from drug administration , distribution, interaction with receptor or target site to
produce biological response. Optimum hydrophobicity is required to transport drug to the site
of action. It is measured experimentally by testing drugs relative distribution, known as Partition
Coefficient.
Partition Coefficient
The hydrophobic character of a drug can be measured experimentally by testing the drug's relative
distribution in an octanol/water mixture. Hydrophobic molecules will prefer to dissolve in the
octanol layer of this two-phase system, whereas hydrophilic molecules will prefer the aqueous
layer. The relative distribution is known as the partition coefficient (P) and is obtained from the
following equation: It is expressed as Log P
𝑪𝒐𝒄𝒕𝒂𝒏𝒐𝒍
P= 𝑪𝒘𝒂𝒕𝒆𝒓

P is generally expressed as Log P because it depends upon various Functional groups along with
whole molecule.
Hydrophobic compounds will have a high P value, whereas hydrophilic compounds will have a
low P value. Varying substituents on the lead compound will groduce a series of analogues having
different hydrophobicities and therefore different P values. By plotting these P values against the
biological activity of these drugs, it is possible to see if there is any relationship between the two
properties. The biological activity is normally expressed as 1/C, where C is the concentration of
drug required to achieve a defined level of biological activity. (The reciprocal of the concentration
(1/C) is used, since more active drugs will achieve a defined biological activity at lower
concentration.)

Substituent Hydrophobicity constant ()

The contribution of hydrophobicity by substituent is expressed as ()
We have seen how the hydrophobicity of a compound can be quantified by using the partition
coefficient P. However, in order to get P we have to measure it experimentally and that means that
we have to synthesize the compounds. It would be much better if we could calculate P theoretically
and decide in advance whether the compound is worth synthesizing. QSAR would then allow us
to target the most promising looking structures. The substituent hydrophobicity constant is a
measure of how hydrophobic a substituent is, relative to hydrogen. The value can be obtained as
follows. Partition coefficients are measured experimentally for a standard compound with and
without a substituent (X). Sum of () is Log P

Log P = ∑ (
 • For example;

2 Electronic factor
The electronic effects of various substituents will clearly have an effect on a drug's ionization or
polarity. This in turn may have an effect on how easily a drug can pass through cell membranes or
how strongly it can bind to a receptor. It is therefore useful to have some measure of the electronic
effect a substituent can have on a molecule. As far as substituents on an aromatic ring are
concerned, the measure used is known as the Hammett substitution constant which is given the
symbol a. The Hammett substitution constant (a) is a measure of the electron withdrawing or
electron donating ability of a substituent and has been determined by measuring the dissociation
of a series of substituted benzoic acids compared to the dissociation of benzoic acid itself.
Hammet Constant ()
It is a measure of Electron-Withdrawing or Electron-Donating ability of a substituent.  value
depends on inductive and resonance effects.  Also depends on whether the substituent is meta
or para substituted.
𝑲𝒙
𝒙 = 𝒍𝒐𝒈 = log 𝑲𝒙 - log 𝑲𝑯
𝑲𝑯

3. Steric factors
In order for a drug to interact with an enzyme or a receptor, it has to approach, then bind to a
binding site. The bulk, size, and shape of the drug may have an influence on this process. For
example, a bulky substituent may act like a shield and hinder the ideal interaction between drug
and receptor. Alternatively, a bulky substituent may help to orientate a drug properly for maximum
receptor binding and increase activity.
Hansch equation
the biological activity of most drugs is related to a combination of physico chemical 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 more than one parameter are more common. These equations are known as
Hansch equations and they usually relate biological activity to the most commonly used
physicochemical properties (P and/or TT, a, and a steric factor).
The Craig plot
Although tables of π and sigma
factors are readily available for a
large range of substituents, it is
often easier to visualize the
relative properties of different
substituents by considering a plot
where the y axis is the value of the
sigma factor and the x axis is the
value of the π factor. Such a plot is
known as a Craig plot. There are
several advantages to the use of
such a Craig plot.