QSAR

Quantitative Structure-Activity
Relationship
Quantitative structure-activity relationships are
mathematical relationships linking chemical structure
and biological activity in a quantitative manner for a
series of compounds.
• Quantitative structure-activity relationships
(QSAR) derive models which describe the
structural dependence of biological
activities either by physicochemical
parameters (Hansch analysis), by indicator
variables encoding different structural
features(Free Wilson analysis), or by three-
dimensional molecular property profiles of
the compounds (comparative molecular
field analysis, CoMFA).
 Physicochemical properties
1. Hydrophobicity
• The hydrophobic character of a drug is crucial to how easily it
crosses cell membranes and may also be important in receptor
interactions.
• The partition coefficient (P): The relative distribution of drug in an
octanol/water mixtre is known as partition coefficient (P)

• The substituent hydrophobicity constant (π):

partition coefficients can be calculated by knowing the contribution
that various substituents make to hydrophobicity. This contribution
is known as the substituent hydrophobicity constant (π).
2. Electronic effects

• The electronic effects of various substituents will clearly have an

effect on a drug's ionization or polarity.
• The Hammett substitution constant (σ) 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.
Benzoic acid is a weak acid and only partially ionizes in water
When a substituent is present on the aromatic ring, this equilibrium is affected.
Electron withdrawing groups, such as a nitro group, result in the aromatic ring
having a stronger electron withdrawing and stabilizing influence on the
carboxylate anion.

The equilibrium will therefore shift more to the ionized form such that the
substituted benzoic acid is a stronger acid and has a larger Kx value (X
represents the substituent on the aromatic ring) (Fig. 9.8).

If the substituent X is an electron donating group such as an alkyl group, then

the aromatic ring is less able to stabilize the carboxylate ion. The equilibrium
shifts to the left and a weaker acid is obtained with a smaller Kx value (Fig. 9.8).
• The Hammett substituent constant (σx) for a particular substituent
(X) is defined by the following equation:

Benzoic acids containing electron withdrawing substituents will have larger KX

values than benzoic acid itself (KH) and therefore the value of σx for an electron
withdrawing substituent will be positive. Substituents such as Cl, CN, or CF3
have positive a values.
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.
• Taft's steric factor (Es)
• Attempts have been made to quantify the steric features of
substituents by using Taft's steric factor (Es). However, the number
of substituents which can be studied by this method is restricted.

• K = Rate of acid hydrolysis of substituted ester

K0 = Rate of acid hydrolysis of parent ester
• Molar refractivity (MR)
• Another measure of the steric factor is provided by a parameter
known as molar refractivity (MR).
• This is a measure of the volume occupied by an atom or group of
atoms.
• The molar refractivity is obtained from the following equation:
 QUANTITATIVE MODELS
• Linear Free Energy Related Method (LFER)
• The interaction of drug molecule with biological system examined by thermodynamic
method is known as Linear Free Energy Related Method (LFER)
• The correlation of biological activity with physicochemical properties is often termed
an extrathermodynamic relationship.
– Because it follows in the line of Hammett and Taft equations that correlate thermodynamic and
related parameters, it is appropriately labeled.

ΔBA = f (ΔL/ΔH, ΔE, ΔEs)

depending upon circumstances, this equation can be modified as,
log BA = bπ + a
= c pKa + a
= dEs + a
= bπ + c pKa + a
= bπ + d Es + a
= bπ + c pKa + d Es + a

• The Hammett equation represents relationships between the logarithms of rate or

equilibrium constants and substituent constants.
• The linearity of many of these relationships led to their designation as linear free
energy relationships.
• The Hansch approach represents an extension of the Hammett equation from
physical organic systems to a biological milieu.
 a. Hansch model
• In 1969, Corwin Hansch extends the concept of linear free energy
relationships (LFER) to describe the effectiveness of a biologically
active molecule.
• It is one of the most promising approaches to the quantification of
the interaction of drug molecules with biological system.
• It is also known as linear free energy (LFER) or extra
thermodynamic method which assumes additive effect of various
substituents in electronic, steric, hydrophobic, and dispersion data in
the non-covalent interaction of a drug and biomacromolecules.

• This method relates the biological activity within a homologous

series of compounds to a set of theoretical molecular parameters
which describe essential properties of the drug molecules.
• Hansch proposed that the action of a drug as depending on two
processes.
• 1. Journey from point of entry in the body to the site of action
– which involves passage of series of membranes and therefore it is related
to partition coefficient log P (lipophilic) and can be explained by random
walk theory.

• 2. Interaction with the receptor site which in turn depends on,

– a) Bulk of substituent groups (steric)
– b) Electron density on attachment group (electronic)
• He suggested linear and non-linear dependence of biological activity
on different parameters.

• Where a-e are constants determined for a particular biological

activity by multiple regression analysis. Log P, σ, Es etc, are
independent variables whose values are obtained directly from
experiment or from tabulations.
• Other parameters than those shown may also be included. If there
are ‘n’ independent variables to be considered, then there are 2n-1
combinations of these variables that may be used to best explain
the tabulated data.
• Nonlinear Models
• Extensive studies on development of linear models led Hansch and
coworkers to note that a breakdown in the linear relationship
occurred when a greater range in hydrophobicity was assessed with
particular emphasis placed on test molecules at extreme ends of
the hydrophobicity range.
• Thus, Hansch et al. suggested that the compounds could be
involved in a"random-walk"process:
– low hydrophobic molecules had a tendency to remain in the first aqueous
compartment, whereas highly hydrophobic analogs sequestered in the first
lipoidal phase that they encountered. This led to the formulation of a
parabolic equation, relating biological activity and hydrophobicity
In the random-walk process, the compounds partition in and out of
various compartments and interact with myriad (number of ) biological
components in the process. To deal with this conundrum (problem),
Hansch proposed a general, comprehensive equation for QSAR

The optimum value of logP for a given system is log Po and it is highly
influenced by the number of hydrophobic barriers a drug encounters in its
walk to its site of action
• Advantages
• easier and inexpensive method
• Has wide applications
• Descriptors like σ,π,Es,MR
– used to predict the biological activity
• Disadvantages
• Extrapolation may give false prediction
• Small molecular model do not necessarily
fit into complex biological system
 Free Wilson Analysis
• The Free-Wilson approach is truly a
structure-activity based methodology
because it incorporates the contribution
made by various structural fragments to
the overall biological activity.
• Log 1/C = contribution of unsubstituted parent
compound + contribution of corresponding
substituents

• Log 1/C =    aij

where,   overall average

i= number of position at which substitution occurs
and
j = is the number substituents at that position
• Method is preferred when nothing is
known about the mode of action or when
the physicochemical properties of the
substituents used unknown.
• Best results obtained in series
– several position available for substitution and
– only if each substituent at any location is
present in at least two compounds of the
series
• Example acetylenic carbamates having
antitumour activity.

BA= f (R) + f (R1) + f (R2) + f (R3) + 

•  biological activity of unsubstituted acetylenic

carbamate.
 Basic assumptions for the use of
the Free-Wilson approach
• approach can be applied to a homologous series
having a common skeleton
• various derivaties can be prepared by using
different substituents at the same distinct
positions of the parent skeleton.
• while choosing drivatives for the synthesis, care
has to be taken that every substituents appears
at least twice at the same positon.
• It reduce the number of compounds to be
synthesized.
 Advantages of Free-Wilson
approach
• it is a simple, fast and cheap method
where no substitution constants like, pi,
sigma, Es etc. were considered.
• Efficiency of this method is high because
greater complexity of the structure, the
larger is the number of possible
substituents at desired positions.
• At each position, the contribution of each
substituents can clearly be identified.
– substituents which can or cannot fulfil the
principle of additivity, can be recognised.
• The Free-Wilson method is effective
especially when substituent constants are
not available.
 Disadvantages
• The large number of molecules with varying substituent
combinations that are needed for this analysis.
• The inability of the system to handle non-linearity of the
dependency of activity on substituent properties.
• Intramolecular interactions between the substituent are
not handled very well, although special treatments can
be used to accommodate proximal effects.
• Extrapolation outside of the substituents used in the
study is not feasible.
• Another problem inherent with this approach is that
usually a large number of variables is required to
describe a smaller number of compounds.