Medicinal Chemistry-III

Quantitative Structure Activity
Relationship (QSAR)

www.DuloMix.com 1
Quantitative Structure Activity Relationship
• Change in physico-chemical properties will affect the ADME

• QSAR approach help in deciding which substituents to be used

• Identify and quantify the physic-chemical properties which can influence the drug
action

• Derive a mathematical equation

• It allows the medicinal chemist for some level of prediction

• Has two advantages- shortlist the compounds

• If analogue is not fitting the equation, implies that some other feature is important

www.DuloMix.com 2
Quantitative Structure Activity Relationship
• What are physic-chemical features?

• Refers to any structural, physical or chemical property of a drug

• Any drug will have infinite properties to calculate

• Difficult task to quantify and relate them to biological activity

• Simple and more practical approach is to consider one or two physico-chemical
properties

• Its not possible always

www.DuloMix.com 3
Quantitative Structure Activity Relationship
• Simple example for LogP vs Log(1/C)

• Draw the best possible line through the data points on the graph

• Linear regression analysis by the least squares method

www.DuloMix.com 4
Quantitative Structure Activity Relationship
• If we draw a line through a set of data points, most of the points will be scattered on
either side of the line

• 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

• Verticals are measured and then squared in order to eliminate the negative values

• Squares are then added up to give a total

• Best line through the points will be the line where this total is a minimum

• Equation of the straight line will be y = k1x + k2 where k1 and k2 are constants

• For a perfect fit, r2 = 1. Good fits generally have r2 values of 0.95 or above
www.DuloMix.com 5
Physicochemical properties
• Many physical, structural, and chemical properties which have been studied by the
QSAR approach

• Most commonly studied are hydrophobic, electronic, and steric

• Possible to quantify easily

• Hydrophobic properties can be easily quantified for complete molecules or for
individual substituents

• Electronic and steric properties are more difficult to quantify, and

• Quantification is only really feasible for individual substituents

www.DuloMix.com 6
Hydrophobicity
• Hydrophobic character of a drug is crucial to how easily it crosses cell membranes

• May also be important in receptor interactions

• Changing substituents on a drug may well have significant effects on its hydrophobic
character and hence its biological activity

• Partition coefficient (P)

• Hydrophobic character of a drug can be measured experimentally by testing the
drug’s relative distribution in an octanol/water mixture

• Hydrophobic molecules will prefer to dissolve in the octanol layer

• Hydrophilic molecules will prefer the aqueous layer
www.DuloMix.com 7
Hydrophobicity
• Relative distribution is known as the partition coefficient

• Hydrophobic compounds will have a high P value

• Hydrophilic compounds will have a low P value

• Varying substituents on the lead compound will produce a series of analogues having
different hydrophobicities and therefore different P values

• Plotting these P values against the biological activity of these drugs

• Possible to see if there is any relationship between the two properties
www.DuloMix.com 8
Hydrophobicity
• Biological activity is normally expressed as 1/C

• where C is the concentration of drug required to achieve a defined level of biological
activity

• Reciprocal of the concentration (1/C) is used, since more active drugs will achieve a
defined biological activity at lower concentration

• Graph is drawn by plotting log (1/C) versus log P

• Relationship between hydrophobicity and biological activity

www.DuloMix.com 9
Hydrophobicity
• Binding of drugs to serum albumin is determined by their hydrophobicity

• Equation shows that serum albumin binding increases as log P increases

• Hydrophobic drugs bind more strongly to serum albumin than hydrophilic drugs

• Knowing how strongly a drug binds to serum albumin can be important in estimating
effective dose levels for that drug

• When bound to serum albumin, the drug cannot bind to its receptor

• Straight-line relationship between logP and biological activity is observed in many
QSAR studies
www.DuloMix.com 10
Hydrophobicity

www.DuloMix.com 11
Hydrophobicity
• General anaesthetics have a simple mechanism of action based on the efficiency
with which they enter the central nervous system (CNS)

• Most potent barbiturates for sedative and hypnotic activity are found to have logP
values close to 2

• Drugs which are to be targeted for the CNS should have a log P value of
approximately 2

• Drugs which are designed to act elsewhere in the body should have logP values
significantly different from 2 in order to avoid possible CNS side-effects

www.DuloMix.com 12
Hydrophobicity
• Cardiotonic agent is producing bright visions in some patients, entering CNS

• log P value of the drug was 2.59

• 4-OMe group was replaced with a 4-S(O)Me group

• Particular group is approximately the same size as the methoxy group, but more
hydrophilic

• logP value of the new drug (sulmazole) was found to be 1.17

www.DuloMix.com 13
Hydrophobicity constant (Π)
• hydrophobicity of a compound can be quantified by using the partition coefficient P

• It would be much better if we could calculate P theoretically and decide in advance
whether the compound is worth synthesizing

• QSAR would then allow us to target the most promising looking structures

• For example, planning to synthesize a range of barbiturate structures

• calculate log P values for them all and concentrate on the structures which had logP
values closest to the optimum logP0 value for barbiturates

• partition coefficients can be calculated by knowing the contribution that various
substituents make to hydrophobicity
www.DuloMix.com 14
Hydrophobicity constant (Π)
• contribution is known as the substituent hydrophobicity constant (Π)

• measure of how hydrophobic a substituent is, relative to hydrogen

• Partition coefficients are measured experimentally for a standard compound with
and without a substituent (X)

• hydrophobicity constant (ΠX) for the substituent (X) is then obtained using the
following equation

www.DuloMix.com 15
Hydrophobicity constant (Π)
• PH is the partition coefficient for the standard compound, and Px is the partition
coefficient for the standard compound with the substituent

• positive value indicates that the substituent is more hydrophobic than hydrogen

• negative value indicates that the substituent is less hydrophobic

www.DuloMix.com 16
Hydrophobicity constant (Π)
• can be used to calculate how the partition coefficient of a drug would be affected by
adding these substituents

• consider the log P values for benzene (log P = 2.13), Chlorobenzene (logP = 2.84), and
benzamide (logP = 0.64)

• benzene is the parent compound, the substituent constants for Cl and CONH2 are
0.71 and —1.49

• it is now possible to calculate the theoretical logP value for meta-chlorobenzamide
and observed is 1.51

www.DuloMix.com 17
Hydrophobicity constant (Π)
• It should be noted that TT values for aromatic substituents are different from those
used for aliphatic substituents

• accurate only for the structures from which they were derived

www.DuloMix.com 18
P vs Π
• Both are not exactly equivalent

• different equations would be obtained with different constants

• partition coefficient P is a measure of the drug’s overall hydrophobicity

• Π factor measures the hydrophobicity of a specific region on the drug’s skeleton

• Most QSAR equations will have a contribution from P or from TT or from both

• study on antimalarial drugs showed very little relationship between antimalarial
activity and hydrophobic character

• these drugs are acting in red blood cells

www.DuloMix.com 19
Electronic effects
• electronic effects of various substituents will clearly have an effect on a drug’s
ionization or polarity

• In turn may have an effect on how easily a drug can pass through cell membranes or
how strongly it can bind to a receptor

• measure used is known as the Hammett substitution constant which is given the
symbol σ

• 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
www.DuloMix.com 20
Hammett substitution constant (σ)
• 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 donating and electron withdrawing substituents

• 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

• equilibrium shifts to the left and a weaker acid is obtained with a smaller Kx value

www.DuloMix.com 21
Hammett substitution constant (σ)
• Hammett substituent constant for a particular substituent (X) is defined by the
following equation

www.DuloMix.com 22
Hammett substitution constant (σ)
• Value of σ x for an electron donating substituent will be negative

• Hammett substituent constant for H will be zero

• Hammett constant takes into account both resonance and inductive effects

• value of σ for a particular substituent will depend on whether the substituent is meta
or para

• Indicated by the subscript m or p after the a symbol

• For example, the nitro substituent has σp = 0.78 and σm = 0.71

• At the para position inductive and resonance both play a part and so the σp value is
greater
www.DuloMix.com 23
Hammett substitution constant (σ)

www.DuloMix.com 24
Hammett substitution constant (σ)
• At the meta position, the influence is inductive and electron withdrawing

• At the para position, the electron donating influence due to resonance is more
significant

• Tables of constants are available which quantify a substituent’s inductive effect (F)
and its resonance effect (R)

• There are limitations to the electronic constants

• Hammett Substituent Constants cannot be measured for ortho substituents

• Substituents have an important steric, as well as electronic, effect

• Above all is only suitable for drugs containing aromatic rings
www.DuloMix.com 25
Hammett substitution constant (σ)
• A series of aliphatic electronic substituent constants are available

• Obtained by measuring the rates of hydrolysis for a series of aliphatic esters

• Methyl ethanoate is the parent ester and it is found that the rate of hydrolysis is
affected by the substituent X

• Electronic effect is purely inductive

• Electron donating groups reduce the rate of hydrolysis and have negative values

• Electron withdrawing groups increase the rate of hydrolysis and have positive values

www.DuloMix.com 26
Hammett substitution constant (σ)
• Values for methyl, ethyl, and propyl are —0.04, —0.07, and -0.36 respectively

• Values for NMe3+ and CN are 0.93 and 0.53 respectively

• Inductive effect is not the only factor affecting the rate of hydrolysis

• May also have steric effect

• Bulky substituent may ‘shield’ the ester from attack and lower the rate of hydrolysis

www.DuloMix.com 27
Steric factors
• For a drug to interact with an enzyme or a receptor, it has to approach, then bind to a
binding site

• Bulk, size, and shape of the drug may have an influence on this process

• 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

• Quantifying steric properties is more difficult than quantifying hydrophobic or
electronic properties
www.DuloMix.com 28
Taft’s steric factor (Es)
• Highly unlikely that a drug’s biological activity will be affected by steric factors alone

• Attempts have been made to quantify the steric features of substituents by using
Taft’s steric factor

• Number of substituents which can be studied by this method is restricted

• Can be calculated similar to Electronic effects

www.DuloMix.com 29
Molar refractivity (MR)
• Measure of the volume occupied by an atom or group of atoms

• Obtained from the following equation

• n is the index of refraction,

• M W is the molecular weight, and

• d is the density.

• Term MW/d defines a volume, while the (n2 — l)/(n2 + 2) term provides a correction
factor by defining how easily the substituent can be polarized

www.DuloMix.com 30
Verloop steric parameter
• Measuring the steric factor involves a computer programme called STERIMOL

• Calculates steric substituent values from standard bond angles, van der Waals radii,
bond lengths, and possible conformations for the substituent

• Can be measured for any substituent

www.DuloMix.com 31
Key points
Hydrophobicity Hydrophobic compounds have high P value and
Hydrophilic compounds have low P value
Hydrophobicity constant (Π)-
Positive value- hydrophobic; negative value- hydrophilic
Electronic effects Hammett substitution constant (σ)
Aromatic compounds- electron withdrawing groups- positive
Aromatic compounds- electron donating groups- negative
Both resonance and inductive effect is considered
Cannot be measured for ortho substituents
Steric factors Taft’s steric factor (Es)
Molar refractivity
Verloop steric parameter

www.DuloMix.com 32
Hansch analysis
• If biological activity is related to one property, simple equation be drawn up

• Biological activity of most drugs is related to a combination of physicochemical
properties

• Hansch equations- relate biological activity to the most commonly used
physicochemical properties

• If the range of hydrophobicity values is limited to a small range then the equation
will be linear as follows

www.DuloMix.com 33
Hansch analysis
• If the P values are spread over a large range then the equation will be parabolic for
the same reasons

• Constants k1-k5 are determined by computer in order to get the best fitting line

• Not all the parameters will necessarily be significant

• For example, the adrenergic blocking activity of β-halo-(β-arylamines) was related to
Π and a and did not include a steric factor

www.DuloMix.com 34
Hansch analysis
• Equation tells us that biological activity increases if the substituents have a positive Π
value and a negative σ value

• Substituents should be hydrophobic and electron donating

• For example, a series of 102 phenanthrene aminocarbinols were tested for
antimalarial activity and found to fit the following equation

www.DuloMix.com 35
Hansch analysis

www.DuloMix.com 36
Hansch analysis
• Equation tells us that antimalarial activity increases very slightly as the
hydrophobicity of the molecule (P) increases

• Constant of 0.14 is low and shows that the increase is slight

• (logP)2 term shows that there is an optimum P value for activity

• Also shows that activity increases significantly if hydrophobic substituents are
present on ring X and in particular on ring Y

• Could be taken to imply that some form of hydrophobic interaction is involved at
these sites

• Electron withdrawing substituents on both rings are also beneficial to activity, more
so on ring Y than ring X. www.DuloMix.com 37
Hansch analysis
• It is important to choose the substituents carefully to ensure that the change in
biological activity can be attributed to a particular parameter

• For example, drugs which contain an amine group

• Most common reaction is N-alkylation

• If activity increases with the chain length of the substituent, is it due to increasing
hydrophobicity or to increasing size or to both?

• Π and MR are not related much here and suitable for varied substituents
www.DuloMix.com 38
What are descriptors?
Includes molecular weight,
Lipophilicity
Hydrogen bonding donors & acceptors
Molecular connectivity
Molecular topology
Molecular geometry
Stereochemistry

Good descriptors should characterize
molecular properties important for
molecular interactions

Literature suggests that more than 2000
molecular descriptors can be calculated
www.DuloMix.com 39
QSAR

• Success of any QSAR model greatly depends on the

a) choice of molecular descriptors and

b) ability to generate the appropriate mathematical relationship between the
descriptors and the biological activity of interest