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Qsar

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Rahul B S
Rahul B S

The document discusses Quantitative Structure Activity Relationships (QSAR), which attempt to identify and quantify physicochemical properties of drugs that influence biological activity using mathematical equations. It describes key physicochemical properties considered in QSAR like hydrophobicity, electronic effects, and steric effects. Measurement scales for these properties like log P, π, σ, and Es are defined. The Hansch equation is presented as a typical QSAR model relating these factors to biological activity. Craig plots are also introduced to help select substituents for QSAR analysis.

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Quantitative Structure Activity Relationships (QSAR) RAHUL B S M PHARM PART 1 College of pharmaceutical science
CONTENTS INTRODUCTION HYDROPHOBICITY OF MOLECULE HYDROPHOBICITY OF SUBSTITUENTS ELECTRONIC EFFECT STERIC EFFECT HANSCH EQUATION CRAIG PLOT REFERENCES
INTRODUCTION Drug designing.... Principles of drug designing  Improving the binding of drugs  Increasing the selectivity  Reduce side effects  Easy synthesisable  Arrangement functional groups and identification of a pharmacophore
Drug designing... Based on lead molecule  Traditional  Lead compound  Analogue molecules designing new molecule Eg; salicylic acid and aspirin Based on target structure By identifying the structure of drug target Designing by denovo drug designing Based on both leading compound and drug target • Combination of both methods
QSAR QSAR approach attempts to identify and quantify the physicochemical properties of a drug and to see whether any of these properties has an effect on the drug’s biological activity by using a mathematical equation PHYSICOCHEMICAL PROPERTIES • 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
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. o Log P 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 (π) Partition coefficient can be calculated by knowing the contribution that various substituents, is known as substituent hydrophobicity constant(π) • A measure of a substituent’s 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 (π x) for sustituent X. The equation is πx= logPx-logPH
A possitive π value shows that the substituent is more hydrophobic than hydrogen A negative value indicates that the substituent is less hydrophobic. The π value is charecteristic for sustituent. Example: πCl = 0.71 πCONH = -1.49 2
THE SUBSTITUENT HYDROPHOBICITY CONSTANT (π) Cl Log P(theory) = log P(benzene) + πΧλ + πΧΟΝΗ 2 O = 2.13 + 0.71 − 1.49 NH2 = 1.35 meta chlorobenzamideΛογ Π (οβσερϖεδ) = 1.51 • A QSAR equation may include both P and π. • P measures the importance of a molecule’s overall hydrophobicity (relevant to absorption, binding etc) • π identifies specific regions of the molecule which might interact with hydrophobic regions in the binding site
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(σ) this is a measure of electron with-drawing or electron-donating ability of a substituents on an aromatic ring.
σ for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid + COOH COO - + H - [PhCO 2] K H = Dissociation constant = [PhCO 2H]
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 σ 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 σ X = log K X = logK X - logK H KH Negative value
EXAMPLES: σp (NO2) = 0.78 σm (NO2) = 0.71 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
σ value depends on inductive and resonance effects σ 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 substituent’s resonance effects • F - Quantifies a substituent’s inductive effects The constants σ,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 σI • Hydrolysis rates measured under basic and acidic conditions O O Hydrolysis C C + HOMe X CH2 OMe X CH2 OH X= electron donating Rate σI = -ve X= electron withdrawing Rate σI = +ve Basic conditions: Rate affected by steric + electronic factors Gives σI after correction for steric effect Acidic conditions: Rate affected by steric factors only (see Es)
STERIC FACTORS 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.
Taft’s 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 substituent’s 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 π 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 H O C O B1 O B 4 H L
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 1  Log  C  = - k1(logP)2 + k 2 logP + k 3 σ + k 4 Es + k 5
Craig Plot Craig plot shows values for 2 different physicochemical properties for various substituents . . + 1.0 CF3SO 2 . . . .75 . .. . CH3SO2 CN .50 NO2 SF5 .. SO 2NH2 CF3 CH3CO . CONH2 .. .25 OCF3 -2.0 . . -1.6 -1.2 -.8 CO2H -.4 F .4 Cl .8 Br 1.2 I 1.6 2.0 -π . . . +π . . CH3CONH -.25 Me Et t-Butyl OCH3 OH . . NH2 -.50 NMe2 -.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
REFERENCES 1. An introduction to medicinal chemistry by Graham L Patric 3rd edition pagee no:271-298 2. Foye : Principles of medicinal chemistry 3. Burgers medicinal chemistry
Qsar

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Qsar

  • 1. Quantitative Structure Activity Relationships (QSAR) RAHUL B S M PHARM PART 1 College of pharmaceutical science
  • 2. CONTENTS INTRODUCTION HYDROPHOBICITY OF MOLECULE HYDROPHOBICITY OF SUBSTITUENTS ELECTRONIC EFFECT STERIC EFFECT HANSCH EQUATION CRAIG PLOT REFERENCES
  • 3. INTRODUCTION Drug designing.... Principles of drug designing  Improving the binding of drugs  Increasing the selectivity  Reduce side effects  Easy synthesisable  Arrangement functional groups and identification of a pharmacophore
  • 4. Drug designing... Based on lead molecule  Traditional  Lead compound  Analogue molecules designing new molecule Eg; salicylic acid and aspirin Based on target structure By identifying the structure of drug target Designing by denovo drug designing Based on both leading compound and drug target • Combination of both methods
  • 5. QSAR QSAR approach attempts to identify and quantify the physicochemical properties of a drug and to see whether any of these properties has an effect on the drug’s biological activity by using a mathematical equation PHYSICOCHEMICAL PROPERTIES • Hydrophobicity of the molecule • Hydrophobicity of substituents • Electronic properties of substituents • Steric properties of substituents
  • 6. 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.
  • 7.  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
  • 8. 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]
  • 9. • 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
  • 10. 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. o Log P 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
  • 11. THE SUBSTITUENT HYDROPHOBICITY CONSTANT (π) Partition coefficient can be calculated by knowing the contribution that various substituents, is known as substituent hydrophobicity constant(π) • A measure of a substituent’s 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 (π x) for sustituent X. The equation is πx= logPx-logPH
  • 12. A possitive π value shows that the substituent is more hydrophobic than hydrogen A negative value indicates that the substituent is less hydrophobic. The π value is charecteristic for sustituent. Example: πCl = 0.71 πCONH = -1.49 2
  • 13. THE SUBSTITUENT HYDROPHOBICITY CONSTANT (π) Cl Log P(theory) = log P(benzene) + πΧλ + πΧΟΝΗ 2 O = 2.13 + 0.71 − 1.49 NH2 = 1.35 meta chlorobenzamideΛογ Π (οβσερϖεδ) = 1.51 • A QSAR equation may include both P and π. • P measures the importance of a molecule’s overall hydrophobicity (relevant to absorption, binding etc) • π identifies specific regions of the molecule which might interact with hydrophobic regions in the binding site
  • 14. 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(σ) this is a measure of electron with-drawing or electron-donating ability of a substituents on an aromatic ring.
  • 15. σ for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid + COOH COO - + H - [PhCO 2] K H = Dissociation constant = [PhCO 2H]
  • 16. 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 σ X = log K X = logK X - logK H KH Positive value
  • 17. X= electron donating group (e.g. CH3) X X + COOH COO - + H Charge destabilised Equilibrium shifts to left KX < KH σ X = log K X = logK X - logK H KH Negative value
  • 18. EXAMPLES: σp (NO2) = 0.78 σm (NO2) = 0.71 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
  • 19. σ value depends on inductive and resonance effects σ 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 substituent’s resonance effects • F - Quantifies a substituent’s inductive effects The constants σ,R and F can only be used for aromatic substituents
  • 20. Aliphatic electronic substituents • Obtained experimentally by measuring the rates of hydrolyses of aliphatic esters • Purely inductive effects • given by σI • Hydrolysis rates measured under basic and acidic conditions O O Hydrolysis C C + HOMe X CH2 OMe X CH2 OH X= electron donating Rate σI = -ve X= electron withdrawing Rate σI = +ve Basic conditions: Rate affected by steric + electronic factors Gives σI after correction for steric effect Acidic conditions: Rate affected by steric factors only (see Es)
  • 21. STERIC FACTORS 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.
  • 22. Taft’s 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
  • 23. Molar Refractivity (MR) this is a measure of a substituent’s 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 π electrons or lone pair of electrons
  • 24. 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 H O C O B1 O B 4 H L
  • 25. 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 1  Log  C  = - k1(logP)2 + k 2 logP + k 3 σ + k 4 Es + k 5
  • 26. Craig Plot Craig plot shows values for 2 different physicochemical properties for various substituents . . + 1.0 CF3SO 2 . . . .75 . .. . CH3SO2 CN .50 NO2 SF5 .. SO 2NH2 CF3 CH3CO . CONH2 .. .25 OCF3 -2.0 . . -1.6 -1.2 -.8 CO2H -.4 F .4 Cl .8 Br 1.2 I 1.6 2.0 -π . . . +π . . CH3CONH -.25 Me Et t-Butyl OCH3 OH . . NH2 -.50 NMe2 -.75 -1.0 -
  • 27. • 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
  • 28. REFERENCES 1. An introduction to medicinal chemistry by Graham L Patric 3rd edition pagee no:271-298 2. Foye : Principles of medicinal chemistry 3. Burgers medicinal chemistry