# 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

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

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

 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

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,

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

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