Quantitative Structure Activity
Relationships (QSAR)
Dr. Talal Ahmed Awad
1
Introduction
Quantitative SARs (QSAR) is a special case of SARs (when
relationships become quantified).
A quantitative structure-activity relationship (QSAR) correlates
measurable or calculable physical or molecular properties to
some specific biological activity in terms of an equation.
Aims
•To relate the biological activity of a series of compounds to
their physicochemical parameters in a quantitative fashion using
a mathematical formula
Requirements
•Quantitative measurements for biological and physicochemical
properties
2
History of QSAR
•The first application of QSAR is attributed to Hansch (1969),
who developed an equation that related biological activity to
certain electronic characteristics and the hydrophobicity of a set
of structures.
log (1/C) = k1log P - k2(log P)2 + k3s + k4
for: C = minimum effective dose
P = octanol - water partition coefficient
s = Hammett substituent constant
kx= constants derived from regression analysis
3
Physicochemical properties
•Hydrophobic
•Electronic
•Steric properties (size)
Hydrophobicity: The partition coefficient (P)
high P value : Hydrophobic
low P value: hydrophilic
4
• Varying substituents on the lead compound will
produce a series of analogues having different
hydrophobicities and therefore different P values.
Biological activity
• expressed as 1/C or log 1/C,
(C is the concentration of drug required to achieve a
defined level of biological activity)
• 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.
5
Log (1/C) ..
.
. . .
.. .
0.78 3.82 Log P
Log 1 0.75 logP + 2.30
C
• binding of drugs to serum
albumin
• (straight line - limited range of
log P)
• Binding increases as log P
6
increases
Log (1/C)
o
Log P Log P
1
Log - 0.22(logP)2 + 1.04 logP + 2.16
C
• General anaesthetic activity of ethers
• (parabolic curve - larger range of log P
values)
• Optimum value of log P for anaesthetic
7
activity = log P°
The substituent hydrophobicity constant (π)
•is a measure of how hydrophobic a substituent is, relative to hydrogen.
•where PH is the partition coefficient for the standard compound, and Px is
the partition coefficient for the standard compound with the substituent.
•+ve value of π indicates that the substituent is more hydrophobic than
hydrogen.
•-ve value indicates that the substituent is less hydrophobic.
8
Electronic effects
Hammett substituent constant (σ).
• This is a measure of the electron-withdrawing or
electron-donating ability of a substituent.
•σ value is positive for electron withdrawing groups and
it is negative for electron donating groups.
Steric Factors
•Large value: Smaller substituent
•Smaller value: Larger substituent
9
Hansch Equation
•A QSAR equation relating various physicochemical properties to
the biological activity of a series of compounds
•Usually includes log P, electronic and steric factors
•Start with simple equations and elaborate as more structures are
synthesised
•Typical equation for a wide range of log P is parabolic
Log 1 C
- k (log P ) 2 + k logP + k + k Es + k
1 2 3 4 5
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Hansch Equation
Example: Adrenergic blocking activity of b-halo-b-arylamines
Y X
CH CH2 NRR'
1
Log C 1.22 - 1.59 + 7.89
Conclusions:
•Activity increases if p is +ve (i.e. hydrophobic substituents)
•Activity increases if σ is negative (i.e. e-donating substituents)
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Hansch Equation
Example:Antimalarial activity of phenanthrene aminocarbinols
CH2NHR'R"
(HO)HC
1
2
Log - 0.015 (logP) + 0.14 logP + 0.27 X + 0.40 Y + 0.65 X + 0.88 Y + 2.34
C
Conclusions:
•Activity increases slightly as log P (hydrophobicity) increases (note that
the constant is only 0.14)
•Parabolic equation implies an optimum log Po value for activity
•Activity increases for hydrophobic substituents (esp. ring Y)
•Activity increases for e-withdrawing substituents (esp. ring Y)
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• The next stage in the process is to see whether the relationship is
meaningful.
• The regression or correlation coefficient (r) is a measure of how
well the equation explains the variance in activity observed in
terms of the physicochemical parameters present in the equation.
• For a perfect fit, r = 1, in which case the observed activities would
be the same as those calculated by the equation.
• r values greater than 0.9 are considered acceptable.
• The regression coefficient is often quoted as r2, in which case
values over 0.8 are considered a good fit.
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3D-QSAR
• Physical properties are measured for the molecule as a whole
• Properties are calculated using computer software
• No experimental constants or measurements are involved
• Properties are known as ‘Fields’
• Steric field - defines the size and shape of the molecule
• Electrostatic field - defines electron rich/poor regions of
molecule
Notes
•Physical properties are measured for the molecule as a whole
•Properties are calculated using computer software
•No experimental constants or measurements are involved
•Properties are known as ‘Fields’
•Steric field - defines the size and shape of the molecule
•Electrostatic field - defines electron rich/poor regions of molecule
CoMFA
• There are several approaches to 3D-QSAR, but the method
which has gained ascendancy was developed by the company
Tripos and is known as CoMFA (Comparative Molecular Field
Analysis).
• CoMFA methodology is based on the assumption that drug-
receptor interactions are non-covalent and that changes in
biological activity correlate with the changes in the steric
and/or electrostatic fields of the drug molecules.
Defining steric and electrostatic fields
•The steric and electrostatic fields surrounding a molecule can be
measured and defined using the grid and probe method.
• This can be repeated for all the molecules in the 3D QSAR study, but
it is crucial that the molecules must all be correctly aligned.
• Molecular alignment is a crucial step in CoMFA study and the
goodness of the model depends on it.
•This can be done by each of the following methods; by:
– substructure
– pharmacophore, or
– docking.
• Identifying a pharmacophore that is common to all the molecules
can assist in this alignment process.
• The pharmacophore is placed into the grid and its position is kept
constant such that it acts as a reference point when positioning
each molecule into the lattice.
• For each molecule studied, the active conformation and
pharmacophore is identified and then the molecule is placed into
the lattice such that its pharmacophore matches the reference
pharmacophore.
• Once a molecule has been placed into the lattice, the steric and
electrostatic fields around it are measured.
Use of grids in measuring molecular fields
•The most commonly measured molecular fields are steric and
electrostatic. These can be measured by placing a molecule into a
preconstructed 3D lattice or grid (Fig. below).
•The intersections of this lattice are called lattice (or grid) points
and these define the 3D space around the molecule.
•Once a molecule has been placed into the lattice, the steric and
electrostatic fields around it can be measured.
•This is done by placing a probe atom such as a proton or an sp3
hybridized carbocation at each of the grid points in turn, and using
software to calculate the steric and electrostatic interactions
between the probe and the molecule.
Relating shape and electronic distribution to biological activity
•The next stage is to relate these properties to the biological activity
of the molecules.
•In 3D QSAR, the variables for each molecule are the calculated
steric and electronic interactions at a couple of thousand lattice
points.
•For relating activities with fields, Partial least squares (PLS) is used
rather than standard multiple linear regression analysis.
Cross Validation
•An important feature of the analysis is that a structure is deliberately
left out as the computer strives to form some form of relationship.
•Once a formula has been defined, the formula is tested against the
structure which was left out.
•This is called cross validation and tests how well the formula predicts
the biological property for the molecule which was left out.
•At the end of the process, the final equation is obtained.
•The predictability of this final equation is quantified by the cross-
validated correlation coefficient r2, which is usually referred to as q2.
•In contrast to normal QSAR, where r2 should be greater than 0.8,
values of q2 greater than 0.5 are considered significant.
.
. . .
.
Tabulate fields for each
compound at each grid point
Compound Biological Steric fields (S) Electrostatic fields (E)
activity at grid points (001-998) at grid points (001-098)
S001 S002 S003 S004 S005 etc E001 E002 E003 E004 E005 etc
1 5.1
2 6.8
3 5.3
4 6.4
5 6.1
Partial least squares
analysis (PLS)
QSAR equation Activity = aS001 + bS002 +……..mS998 + nE001 +…….+yE998 + z
Contour maps analysis
•It is more useful, though, to give a graphical representation showing
which regions around the molecule are important to biological activity
on steric or electronic grounds.
•Therefore, a steric map shows a series of coloured contours indicating
beneficial and detrimental steric interactions around a representative
molecule from the set of molecules tested.
•A similar contour map is created to illustrate beneficial or detrimental
electrostatic interactions.
