Quantitative Strusture Activity Relitionship

Medicinal Chemistry

Tim 3
Anggun Yunia L Retno Romauli
Delima Nugraha Sri Nurlatipah
Mita Fajriaturrahmah Yulia Andina
Nurmala Mulyani
 Compounds + biological activity

QSAR

New compounds with

improved biological activity

Presented By Deshmukh Md Faizan

1
M. Pharm (2nd Sem)

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY,

R. C. PATEL INSTITUTE OF PHARMACEUTICAL
EDUCATION AND RESEARCH, SHIRPUR
CONTENTS
History of QSAR
Introduction
Objectives
Steps in QSAR
Hansch Analysis
Free Wilson Approach
Mixed Approach
Advantages of QSAR
Disadvantages of QSAR
Application of QSAR
3

Delima
History of QSAR
 Discoverer of the Periodic Table
an early Chemoinformatician

Dmitry Mendelev
(1834 1907)

Russian chemist who arranged the 63 known elements into a periodic table
based on atomic mass, which he published in Principles of Chemistry in
1869. Mendelev left space for new elements, and predicted three yet-to-
be-discovered elements: Ga (1875), Sc (1879) and Ge (1886).
Periodic Table

Chemical properties of elements gradually

vary along the two axis
 History of QSAR

1868, D. Mendeleev The Periodic Table of Elements

1868, A. Crum-Brown and T.R. Fraser formulated a suggestion that

physiological activity of molecules depends on their constitution:
Activity = F(structure)
They studied a series of quaternized strychnine derivatives, some
of which possess activity similar to curare in paralyzing muscle.

1869, B.J. Richardson narcotic effect of primary alcohols varies in

proportion to their molecular weights.
History of QSAR

1893, C. Richet has shown that toxicities of some simple

organic compounds (ethers, alcohols, ketones) were inversely
related to their solubility in water.

1899, H. Meyer and 1901, E. Overton have found variation of

the potencies of narcotic compounds with LogP.

1904, J. Traube found a linear relation between narcosis and

surface tension.
History of QSAR

1937, L.P. Hammett studied chemical reactivity of substituted

benzenes:
Hammett equation,
Linear Free Energy Relationship (LFER)

1939, J. Fergusson formulated a concept linking narcotic

activity, logP and thermodynamics.

1952- 1956, R.W. Taft devised a procedure for separating

polar, steric and resonance effects.
History of QSAR

1964, C. Hansch and T. Fujita: the biologists Hammett

equation.

1964, Free and Wilson, QSAR on fragments.

1970s 1980s development of 2D QSAR (descriptors,

mathematical formalism).

1980s 1990s, development of 3D QSAR (pharmacophores,

CoMFA, docking).

1990s present, virtual screening.

INTRODUCTION
QSAR is an attempt to remove the element of luck from drug design
by establishing a mathematical relationship in the form of an equation
between biological activity and measurable physicochemical
parameters.
QSAR is mathematical relationship between a biological activity of a
molecular system and its geometric and chemical characteristics.
QSAR(Quantitative Structure Activity Relationship) are based on the
assumption that the structure of molecule (i.e. its geometric, steric and
electronic properties) must contain the features responsible for its
physical, chemical and biological properties.
QSAR in simplest terms, is a method for building computational or
mathematical models which attempts to find a statistically significant
correlation between structure and function.
1
1
Retno R.U
OBJECTIVE
QSAR makes it easy now to reach the conclusion for any of
the congener that still not in process, in way that whether it
will optimal and profitable or not.
To predict the biological activities of untested and
sometimes yet unavailable compounds.
To optimize the existing leads so as to improve their
biological activities.
Quantitative relationship between the structure and
physiochemical properties of substances and their
biological activity are being used as the foundation stone in
search of new medicines

1
2
STEPS IN QSAR

1
3
 1. STEPS IN QSAR
(STRUCTURE ENTRY
AND MODELLING )

Structure are sketched using standard drawing software's

commercial or freeware
Molecular modelling for the generation of low energy
conformation
Ab intitio-very small molecule, Highly
accurate, High computational costs.
Software- Gaussian.

Semi-empirical-Medium sized
molecules, accurate but computationally
intensive.
Software- MOPAC.

Molecular Mechanics- No restriction 6

on size, accurate with proper conformational
analysis. Software- CVFF.
2.STEPS IN QSAR (DESCRIPTOR GENERATION)

Physico-chemical properties that describe some aspect of

the chemical structure
Empirical Descriptors:-
determined experimentally NMR chemical shift,
Melting point.
Some of the experimentally determined physico-
chemical parameters:
log P = C or g/ C aqu
x =log P (R-X) log P (R-H)
Theoretical Descriptors:-
Calculated (theoretical) topological ,BCUT.

15
 0D Descriptors:
(i.e. Constitutional Descriptor) molecular weight, no.of
atoms, no of non-H atoms, no. of bonds, no. of heteroatom's,
no. of multiple bonds (nMB), no. of rings, no. of circuits,
no.of H-bond donors, no. of h-bond acceptors, no. of
Nitrogen atoms (nN). Number of certain chemical groups and
functionalities in the molecule. Total no of bonds in the
molecule. Number of rings, no of rings divided by the total
no of atoms.

Classification based on the dimensionality of structure presentation

1D (atom counts, MW, number of functional groups, )

2D (topological indices, BCUT, TPSA, Shannon enthropy, )
3D (geometrical parameters, molecular surfaces, parameters calculated
in quantum chemistry programs, )

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Descriptors from Codessa Pro
Descriptor Families
Topological Descriptors - calculable
molecular attributes that
Fragments govern particular
macroscopic properties
Receptor surface
Structural
Information-content Products
Spatial
Electronic
Thermodynamic
Conformational Plus Molecular and
Quantum Methods
Quantum mechanical
 1D Descriptors:
number of atoms
absolute and relative numbers of C, H, O, S, N, F, Cl, Br, I, P
atoms
number of bonds (single, double, triple and aromatic bonds)
number of benzene rings, number of benzene rings divided by the
number of atoms
molecular weight and average atomic weight
Number of rotatable bonds (All terminal H atoms are ignored)
Hbond acceptor - Number of hydrogen bond acceptors
Hbond donor - Number of hydrogen bond donors
These simple descriptors reflect only the molecular composition of
the compound without using the geometry or electronic structure of
the molecule.

Anggun
2D Descriptors:
Topological Descriptors based on graph theory concepts.
These descriptors have been widely used in QSAR studies.
They help to differentiate the molecules according mostly to
their size.
Graph
representation
Isopentane Graph
Edges
Invariants(topol
Node ogical
descriptors)

Isopentane = Four edges, Five nodes and the adjacency

Relationship implicitly in the structure

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3D Descriptor:
Geometrical Descriptor-
This descriptors using the atomic coordinates (x,y,z) of a
molecules are therefore called 3D descriptors.
Encode the 3D aspect of the structure, Vander Waals
volume, Molecular Surface.
Shadow areas, solvent accessible areas, etc.
Quantum Mechanical Descriptor-
Encode the aspect of the structures that are related to the
electrons.
Electronic descriptor include, HOMO or LUMO
Energies, partial atomic charges, etc.

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Comparative Molecular Field Analysis (CoMFA)
The comparative molecular field analysis a grid based
technique, most widely used tools for three dimensional
structure-activity relationship study.
In this method the molecule-receptor interaction is
represented by the steric and electrostatic field exerted
by each molecule.

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3.STEPS IN QSAR (FEATURE SELECTION AND
MODELLING)
Traditional techniques in feature selection

Multiple Linear Regression Analysis (MLR):

This is computerised method which is correlate the biological activity
with physico-chemical properties. This method check the impact of each
variable (physico-chemical properties) on biological activity.

Principal Component Analysis (PCA):

This is also computerised method, this method is superior than MLR
since, MLR can correlate 5 times of physico-chemical properties than
compounds, but this method PLA correlate all the physico-chemical
properties with biological activity even these physico-chemical
properties are more than the number of compounds. 12
Partial Least Square (PLS):
Modification of the PCA technique, where the dependent
variables are also extracted into a new component as to
maximize the correlation with the extracted component, Has an
additional advantages of modelling multiple dependent
parameters.

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4. STEPS IN QSAR (MODEL VALIDATION)

Selection and Validation of QSAR models

The selection and validation of the QSAR model for virtual
screening is of almost importance and should confer to the
following recommendations-
Careful selection of independentvariables
Significance of the variables (Statistical parameters)
Minimum number of compounds per variable
Importance of the model that corroborates with known
biophysical data.

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 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 1C - k1(logP)2 + k 2 logP + k 3 + k 4 Es + k 5
Nurmala
Craig Plot
Craig plot shows values for 2 different physicochemical
properties for various substituents

. . + 1.0

. .
CF 3SO 2

. .. .. CN
.75
NO2

SF 5

.
SO 2NH2 CH3S O 2 .50 CF 3

..
CH3CO
CONH2

. . .25
OCF 3

. . -.8 -.4
CO2H

.4
Cl Br I

.
-2.0 -1.6 -1.2 .8 1.2 1.6 2.0

.
F

-
. .
CH3CONH +
. OCH3
-.25 Me Et
t-Butyl

.
OH

. NH2
-.50

NMe 2
-.75

-1.0

-
 Allows an easy identification of suitable substituents for
a QSAR analysis which includes both relevant
properties

Choose a substituent from each quadrant to ensure

orthogonality

Choose substituents with a range of values for each

property
 Hansch Analysis

Biological Activity = f (Physicochemical properties ) + constant

Physicochemical properties
can be broadly classiied into
three general types:

Hydrophobicity of the
molecule
Hydrophobicity of
substituents
Electronic properties of
substituents
Steric properties of
substituents
 A range of compounds is synthesized in order to vary one
physicochemical property and to test it affects the bioactivity.

A graph is then drawn to plot the biological activity on the

y axis versus the physicochemical feature on the x axis.

It is necessary to draw the best possible line through the

data points on the graph. This done by procedure known as
linear regression analysis by the least square method.
 If we draw a line through a set of data points will be
scattered on either side of the line. The best line will be the
one closest to the data points.

To measure how close the data points are , vertical lines

are drawn from each point.

Log (1/C)

. . .
.
.. . . .
0.78 3.82 Log P
HYDROPHOBICITY ()
Hydrophobic character of a drug is crucial to how easily it
crosses the cell membrane and may also important in receptor
interactions.

Hydrophobicity of a drug is measured experimentally by

testing the drugs relative distribution in octanol water mixture.
This relative distribution is known as partition coefficient.

Partition Coefficient P = conc. Drug in in octanol]

[Conc.of drug in water]
 Activity of drugs is often related to P

Biological activity log(1/c) = K1 log P + K2

Eg: binding of a drug to serum albumin determined by

hydrophobicity and study of 42 compounds.
(straight line - limited range of log P)

Log (1/C)

. . .
log(1/c) = 0.075 log P + 230
(n= 42, r= 0.960 s= 0.159)
.
.. . . .
0.78 3.82 Log P

Mita
 If the partition coefficient is the only
factor influencing biological activity, the
parabolic curve can expressed by the
equation

Log (1/C)
log(1/c) = -K1 (log P)2 + K2 log P + k3

Few drugs where activity is related to

log P factor alone.
Log P o Log P
QSAR equations are only applicable to
compounds in the same structural class
(e.g. ethers)

However, log Po is similar for

anaesthetics of different structural
classes
THE SUBSTITUENT HYDROPHOBICITY CONSTANT ()

Partition coefficient can be calculated by knowing the

contribution that various substituents, is known as substituent
hydrophobicity constant()

A measure of a substituents hydrophobicity relative to hydrogen

Partition coefficient is measured experimently for a standard

compound such as benzene with or without a substituent (X).

The hydrophobicity constant ( x) for sustituent X.

The equation is
x= logPx-logPH
 A possitive value shows that the substituent is more
hydrophobic than hydrogen

A negative value indicates that the substituent is less

hydrophobic.
The value is charecteristic for sustituent.

Cl = 0.71 CONH2 = -1.49

 THE SUBSTITUENT HYDROPHOBICITY CONSTANT ()

Cl
Log P(theory) = log P(benzene) +
2
O

NH2
meta c h l o r o b e n z a m i d e

A QSAR equation may include both P and .

P measures the importance of a molecules overall
hydrophobicity (relevant to absorption, binding etc)

identifies specific regions of the molecule which might interact

with hydrophobic regions in the binding site
Biological activity as a function of logP
ELECTRONIC EFFECT ()
The electronic effect of various sustituents will clearly have
an effect on drug ionisation and polarity.

Have an effect on how easily a drug can pass through the cell
membrane or how strongly it can interact with a binding site.

Hammet substituent constant() this is a measure of electron

with-drawing or electron-donating ability of a substituents on an
aromatic ring.
 for aromatic substituents is measured by comparing the
dissociation constants of substituted benzoic acids with
benzoic acid

+
COOH COO
-
+ H

[PhCO -2]
K H = Dissociationconstant = [PhCO 2H]

Sri
 X= electron withdrawing group (e.g. NO2,)

X = electron
withdrawing X X
group CO2H CO2 + H

Charge is stabilised by X
Equilibrium shifts to right
KX > KH

X = log
K X = logK
X - logK H
KH

Positive value
X= electron donating group (e.g. CH3)

X X +
COOH COO
-
+ H

Charge destabilised
Equilibrium shifts to left
KX < KH

X = log K X = logK X - logK H

KH

Negative value
 EXAMPLES: p (NO2) m (NO2)

meta-Substitution
O

N
O

e-withdrawing (inductive effect only)

DRUG

para-Substitution

O O O O O O O O
N N N N

e-withdrawing
(inductive +
resonance effects)
DRUG DRUG DRUG DRUG
 Substituent Substituent
Meta Meta Para
Para
-0.708 -1.00 +0.337 +0.062
O F

+0.121 -0.37 +0.373 +0.227

OH Cl

+0.115 -0.268 +0.355 +0.406

OCH3 CO2 H

-0.161 -0.660 +0.376 +0.502

NH2 COCH3

-0.069 -0.170 +0.43 +0.54

CH3 CF3

-0.121 -0.072 +0.61 +0.70

(CH3)3Si SO2 Ph

+0.06 -0.01 +0.710 +0.778

C6 H5 NO2
0.000 0.000 +N(CH ) +0.88 +0.82
H 33

+0.25 +0.15 +1.76 +1.91

SH N2 +
+0.15 0.00 +S(CH ) +1.00 +0.90
SCH3 3 2
 value depends on inductive and resonance effects

value depends on whether the substituent is meta or para

ortho values are invalid due to steric factors

Electronic Factors R & F

R - Quantifies a substituents resonance effects

F - Quantifies a substituents inductive effects

The constants ,R and F can only be used for aromatic substituents

Aliphatic electronic substituents

Obtained experimentally by measuring the rates of hydrolyses

of aliphatic esters
Purely inductive effects
given by I
Hydrolysis rates measured under basic and acidic conditions
O O
Hydrolysis
C C + HOMe
X CH2 OMe X CH2 OH

X= electron donating Rate I = -ve

X= electron withdrawing Rate I = +ve

Basic conditions: Rate affected by steric + electronic factors

Gives I after correction for steric effect
Acidic conditions: Rate affected by steric factors only (see Es)
STERIC FACTORS (Es)

The bulk, size and shape of a drug will influence how easily it can
approach and interact with binding site.

A bulky substituents may act like a shield and hinder the ideal
interaction between a drug and its binding site.

Bulky substituent may help to orient a drug properly for

maximum binding and increase activity.

Yulia Andin
Tafts Steric Factor (Es)

Measured by comparing the rates of hydrolysis of substituted

aliphatic esters against a standard ester under acidic conditions
Es = log kx - log ko

kx represents the rate of

hydrolysis of a substituted ester
ko represents the rate of hydrolysis of the parent ester

Limited to substituents which interact sterically with the

tetrahedral transition state for the reaction
Not by resonance or hydrogen bonding

Disadvantages
ES value measures intramolecular steric effect but drugs interact
with target binding site in intermolecular process (i.e. a drug
Molar Refractivity (MR)
this is a measure of a substituents volume

(n 2 - 1) mol. wt.
MR = x
(n 2 - 2) density

Correction factor Defines volume

for polarisation
(n=index of
refraction)

This is perticularly significant if the substituent has

electrons or lone pair of electrons
Verloop Steric Parameter

- calculated by software (STERIMOL)

- gives dimensions of a substituent from the standard
bond angle ,van der Waals radii, bond length and possible
conformations for the substituents
- can be used for any substituent
Example - Carboxylic acid

B4 B3

O B
3

B2
C
B1
O H O C O
B
4

L
Es Values for Various Substituents
H Me Pr t-Bu F Cl Br OH SH NO2 C6H5 CN NH2

0.0 -1.24 -1.60 -2.78 -0.46 -0.97 -1.16 -0.55 -1.07 -2.52 -3.82 -0.51 -0.61

Compare some extreme values:

H 0.00 the reference substituent in the Taft equation

Me -1.24: little steric resistance to hydrolysis
t-Bu -2.78 : large resistance to hydrolysis

Note: H is usually used as the reference substituent (Es(0)), but sometimes when another
group, such as methyl (Me) is used as the reference, as in the chemical equation above, the
value becomes 1.24.
What do these Drugs have in Common?

Cl NH2 Cl Chloroform
N LogPo/w = 1.97
Cl Cl
N
N O
O O
Cl NH2 H Secobarbital
N
Irsogladine O LogPo/w = 1.97
LogPo/w = 1.97 N
H
H O

H
OH
O O
H Trandolapril
O H
O O H LogPo/w = 1.97
OO
OH O N
H
OH OH H N OH
O
H
O
Acetyldigitoxine O O
H
LogPo/w = 1.97
3D Hydrophobicity

hydrophobic hydrophilic

All molecules have the same logP ~1.5, but different 3D MLP pattern.
 Example of oral administration:

Drug is exposed to a large variety

of pH values:
Saliva pH 6.4
Stomach pH 1.0 3.5
Duodenum pH 5 7.5
Jejunum pH 6.5 8
Colon pH 5.5 6.8
Blood pH 7.4
Liver-first-pass-effect

www.3dscience.com
APPLICATION OF QSAR
Prediction of activity.
Prediction of toxicity.
Lead compound optimization.

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Software
 DRAGON

The software DRAGON calculates 1664 molecular descriptors divided

in 20 blocks
 CODESSA Pro

calculate a large variety of molecular descriptors on the basis of the 3D

geometrical structure and/or quantum-chemical parameters;
develop (multi)linear and non-linear QSPR
 ISIDA program

calculates fragment descriptors;

develop (multi)linear and non-linear QSPR models
REFERENCE
1. Graham L. Patrick, 2001. An Introduction to Medicinal Chemistry,
Oxford University Press, Page no.258-270.
2. Ashutosh Kar. 2005. Medicinal Chemistry, New Age International
Publishers, Page no.19-33
3. Dr. V. M. Kulkarni, Dr. K.G. Bothara, 2006. Drug Design, Nirali
Prakashan, Page no.8.25-8.27.
4. An introduction to medicinal chemistry by Graham L Patric 3rd
edition pagee no:271-298
5. Foye : Principles of medicinal chemistry
6. Burgers medicinal chemistry

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HATUR NUHUN