Quantitative structure-activity relationship (QSAR) is a computational modeling method for revealing relationships between structural properties of chemical compounds and biological activities

1. Quantitative Structure - Activity
Relationships (QSAR)

2. Rationale for QSAR Studies
• The in vitro and in vivo activity of a substance depends on some biological
parameters, including the intrinsic reactivity of the drug, its solubility in
water, its ability to pass the blood-brain barrier, its non- reactivity with
non-target molecules that it encounters on its way to the target, and others.
• QSAR correlates measurable or calculable physical or molecular properties of
the drug molecules with these specific biological parameters in terms of an
equation.
• These parameters have major influence on the drug’s activity. QSAR derived
equation take the general form:
Biological activity = function (parameters)

3. Functions of QSAR
• Once a valid QSAR has been determined, it should be possible to
predict the biological activity of related drug candidates before they
are put through expensive and time-consuming biological testing.
• Activity is expressed as log(1/C). C is the minimum concentration
required to cause a defined biological response, which can be
determined by QSAR.

4. Parameters
• 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.

5. Hansch’s Approach in Evaluating
Hydrophobicity
The first application of QSAR is attributed to Hansch (1969), who
developed an equation that relates biological activity to hydrophobicity
of a set of structures.
log (1/C) = k1log P - k2(log P)2 + k3σ + k4
Here,
C = Minimum effective dose
Log P = Partition coefficient
σ = Hammett substituent constant
kx= Constants derived from regression analysis
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6. Hansch’s Approach in Evaluating Hydrophobicity
• Log P is a measure of the drug’s hydrophobicity, which was selected
as a measure of its ability to pass through cell membranes.
• The log P (or log Po/w) value reflects the relative solubility of the drug
in octanol (representing the lipid bilayer of a cell membrane) and
water (the fluid within the cell and in blood).
Log P = Log K (o/w) = Log ([X]octanol/[X]water)
• Log P values may be measured experimentally or, more commonly,
calculated.
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7. Molecular Properties in QSAR
Many other molecular properties have been incorporated into QSAR studies;
some of these are measurable physical properties, such as:
 Density
 pKa
 Ionization energy
 Boiling point
 Hvaporization
 Hhydration
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 Dipole moment (m)
 Refractive index
 Reduction potential
 Molecular weight
 Lipophilicity parameter

8. Molecular Properties in QSAR
Other molecular properties (descriptors) that have been incorporated into
QSAR studies are calculated properties, such as:
• Ovality  Surface area
• HOMO energy  LUMO energy
• Polarizability  Charges on individual atoms
• Molecular volume  Solvent accessible surface area
• Van-der-Waals surface area  Maximum (+) and (-) charge
• Molar refractivity  Hardness
• Hydration energy  Taft’s steric parameter
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