1.

QUANTITATIVE STRUCTURE
ACTIVITY RELATIONSHIP(QSAR)

Dr. P. Valentina
Professor & HOD
Department of Pharmaceutical Chemistry
SRM College of Pharmacy
 INTRODUCTION
y QSAR involves the derivation of mathematical formula
which relates the biological activities of a group of
compounds to their measurable physicochemical
parameters. These parameters have major influence on the
drug’s activity. QSAR derived equation take the general
form:
Biological activity= function(parameters)
y Activity is expressed as log(1/c). C is the minimum
concentration required to cause a defined biological
response.
 PARAMETERS
‰ The parameter is the measure of the potential contribution
of its group to a particular property of the parent drug.

Various parameters used in QSAR studies are

1. Lipophilic parameters: partition coefficient, π-substitution
constant
2. Polarizability parameters: molar refractivity, parachor
3. Electronic parameters: Hammet constant, dipole moment.
4. Steric parameters: Taft’s constant.
5. Miscellaneous parameters: molecular weight, geometric
parameters.
 LIPOPHILIC PARAMETERS
y Lipophilicity is partitioning of the compound between an
aqueous and non-aqueous phase.
Partition coefficient:
¾ P = [drug] in octanol / [drug] in water
¾ Typically over a small range of log P, e.g. 1-4, a straight
line is obtained
e.g. log 1/C = 0.75 log P + 2.30
¾ If graph is extended to very high log P values, then get a
parabolic curve
log 1/C = - k1 (log P)2 + k2 log P + k3
¾ When P small, dominated by log P term

¾ When P large, log P squared dominates & so activity

decreases
π-substituent constant or hydrophobic substituent
constants:
y The π-substituent constant defined by hansch and co-workers
by the following equation.
px = log Px - log PH
y A positive πvalue indicates that the πsubstituent has a higher
lipophilicity than hydrogen and the drug favours the organic
phase.
y A negative πvalue indicates that the πsubstituent has a lower
lipophilicity than hydrogen and the drug favours the aqueous
phase.
 ELECTRONIC PARAMETERS
The Hammett constant(σ);
sx = log (Kx/Kbenzoic)
Electron Withdrawing Groups
y Equilibrium shifts Right & Kx > Kbenzoic

y Since sx = log Kx – log Kbenzoic, then s will be positive .

y Hammett constant takes into account both resonance and
inductive effects; thus, the value depends on whether the
substituent is para or meta substituted
-ortho not measured due to steric effects.
 STERIC SUBSTITUTION CONSTANT
y 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.
much harder to quantitate
y Examples are:
y Taft’s steric factor (Es) (~1956), an experimental value based
on rate constants
y Molar refractivity (MR)--measure of the volume occupied by
an atom or group--equation includes the MW, density, and the
index of refraction--
y Verloop steric parameter--computer program uses bond angles,
van der Waals radii, bond lengths
 HANSCH ANALYSIS
Proposed that drug action could be divided into 2 stages:
1) Transport & 2) Binding
Each of these stages depend upon the physical and
chemical properties of the drug.
Log 1/C = k1P = k2P2 + k3s + k4Es + k5

Look at size and sign for each component of the equation.

Values of r <<0.9 indicate equation not reliable
Accuracy depends on using enough analogs, accuracy of
data, & choice of parameters
Applications: used to predict the activity of an as yet
unsynthesized analouge.
 FREE WILSON ANALYSIS
y This method is based on the assumption that the
introduction of a particular substituent at a particular
molecular position , always leads to a quantitatively similar
effect on biological potency of the whole molecules and
expressed by the equation as
y BA= μ+Σ aj
y Application:
y Easy to apply
y Simple method
y The substituent which can not fulfill the principle of
additivity can be recognized
y Effective when substituent constants are not available.
 TOPLISS METHOD
™ This approach is completely non-mathematical and non-
statistical and does not need computerization of the data.
™ A Topliss scheme is a flow diagram that in a series of steps
directs the medicinal chemist to produce a series of analogues,
some which have greater activity than lead used to start the tree.
™ There are two topliss schemes
1. For the aromatic substituents
2. For the aliphatic side chain substituents.
Applications:
This method can be used if synthetic route might be difficult
and only a very few structures can be made in a limited time
COMPUTER AIDED DRUG
DESIGN(CADD)
 COMPUTER AIDED DRUG DESIGN(CADD)
y Computers are an essential tool in the modern medicinal chemistry
and are important in both drug discovery and development.
MOLECULAR MODELING:
y Molecular modeling is a general term that covers a wide range of
molecular mechanics and computational chemistry techniques used
to build, display, manipulate, simulate and analyze molecular
structure and to calculate properties of those structures.
y Molecular modeling techniques can be divided into molecular
graphics and computation chemistry.
 MOLECULAR GRAPHICS
y It is the core of modeling system, providing for the
visualization of molecular structure and its properties.
y In molecular modeling the data produced are converted
into visual image on the computer screen by graphic
packages.
y These images can be displayed in a variety of styles like
space fill, stick, ball and stick etc.
y Ribbon presentation is used for large large molecules like
nucleic acid and protein.
 MOLECULAR MECHANICS
y In this technique the energy of structure is calculated.
y The equation used in molecular mechanics follow the law of
classical physics and applies to the molecular nuclei without
consideration of the electrons.
y It assumes that the total potential energy in a molecule is given
by the sum of all the energies of the attractive and repulsive
forces between the atoms in the structure.
y E total= Σ Estretching + Σ Ebend + Σ Etorsion + Σ Evdw + Σ
Ecoulombic
Advantages:
1. Less time consuming
2. Simple to use
 MOLECULAR DYNAMICS
y Molecular dynamics programs allow the modular to show
the dynamic nature of the molecule by simulating the
natural motion of the atom in a structure.
y The velocities of the atoms are related directly to
temperature.
y Higher temperature stimulations are used to search
conformational shape
y Molecular dynamics can also be used to find minimal
energy structure and conformational analysis
Ex: conformational analysis of butane
 QUANTUM MECHANICS
y It is based on the realization that electrons and all material
particles exhibit wave like properties.
HΨ= EΨ
y EΨ represents the total potential and kinetic energy of all the
particles in the structure.
y H is the Hamiltonium operator acting on the wave function.
y Quantum mechanical methods are suitable for calculating the
following
1. Heat of formation
2. Dipole moments
3. Electrostatic potentials
4. Bond dissociation energies
5. Transition stage geometries and energies.