Quantitative Structure Activity Relationship (QSAR) - Medicinal Chemistry III B. Pharma 6th Semester

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

       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

       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

       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

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


       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

       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

       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

       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

       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

       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

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

       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

       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

       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

       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

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

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

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

       Hammett substituent constant for a particular substituent (X) is defined by the following equation

       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

       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

       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

       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

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

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

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 (n2l)/(n2 + 2) term provides a correction factor by defining how easily the substituent can be polarized

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

Key points


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

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

       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

       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

       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.

       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

What are descriptors?

Includes molecular weight,


Hydrogen bonding donors & acceptors

Molecular connectivity

Molecular topology

Molecular geometry


Good descriptors should characterize molecular properties important for molecular interactions

Literature suggests that more than 2000 molecular descriptors can be calculated  


       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



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