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
• PHis 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 CONH2are 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 (n2 — l)/(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)2term 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
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