QSAR

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QSAR
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Introduction

• Aims
• To relate the biological activity of a series of
  compounds to their physicochemical parameters in
  a quantitative fashion using a mathematical
  formula
• Requirements
• Quantitative measurements for biological and
  physicochemical properties
• Physicochemical Properties

• Hydrophobicity of the molecule
• Hydrophobicity of substituents
• Electronic properties of substituents
• Steric properties of substituents

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Hydrophobicity of the Molecule
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Hydrophobicity of the Molecule

• Activity of drugs is often related to P
• e.g. binding of drugs to serum albumin
• (straight line - limited range of log P)

• Binding increases as log P increases
• Binding is greater for hydrophobic drugs

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Hydrophobicity of the Molecule
Example 2 General anaesthetic activity of
ethers (parabolic curve - larger range of log P
values)
Optimum value of log P for anaesthetic activity
log Po
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Hydrophobicity of the Molecule

• 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 (ca. 2.3)
• Structures with log P ca. 2.3 enter the CNS
  easily
• (e.g. potent barbiturates have a log P of
  approximately 2.0)
• Can alter log P value of drugs away from 2.0 to
  avoid CNS side effects

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Hydrophobicity of Substituents - the substituent
hydrophobicity constant

• A measure of a substituents hydrophobicity
  relative to hydrogen
• Tabulated values exist for aliphatic and aromatic
  substituents
• Measured experimentally by comparison of log Ps
  with parent structure

Example

• Positive values imply substituents are more
  hydrophobic than H
• Negative values imply substituents are less
• hydrophobic than H

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Hydrophobicity of Substituents - the substituent
hydrophobicity constant

• The value of p is only valid for parent
  structures
• It is possible to calculate log P using p values

• A QSAR equation may include both P and p.
• P measures the importance of a molecules overall
  hydrophobicity (relevant to absorption, binding
  etc)
• p identifies specific regions of the molecule
  which might interact with hydrophobic regions in
  the binding site

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Electronic Effects Hammett Substituent Constant

• The constant (s) a measure of the e-withdrawing
  or e-donating influence of substituents
• It can be measured experimentally and tabulated
• (e.g. s for aromatic substituents is measured by
  comparing the dissociation constants of
  substituted benzoic acids with benzoic acid)

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Hammett Substituent Constant
X electron withdrawing group (e.g. NO2)
Charge is stabilised by X Equilibrium shifts to
right KX gt KH
Positive value
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Hammett Substituent Constant
X electron donating group (e.g. CH3)
Charge destabilised Equilibrium shifts to left KX
lt KH
Negative value
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Hammett Substituent Constant
s value depends on inductive and resonance
effects s value depends on whether the
substituent is meta or para ortho values are
invalid due to steric factors
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Hammett Substituent Constant
EXAMPLES
e-withdrawing (inductive effect only)
e-withdrawing (inductive resonance effects)
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Hammett Substituent Constant
EXAMPLES
e-withdrawing (inductive effect only)
e-donating by resonance more important than
inductive effect
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Hammett Substituent Constant (s)
QSAR Equation
Diethylphenylphosphates (Insecticides)
Conclusion e-withdrawing substituents increase
activity
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Aliphatic electronic substituents

• Defined by sI
• Purely inductive effects
• Obtained experimentally by measuring the rates of
  hydrolyses of aliphatic esters
• Hydrolysis rates measured under basic and acidic
  conditions

Basic conditions Rate affected by steric
electronic factors Gives sI after correction
for steric effect Acidic conditions Rate
affected by steric factors only
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Steric Factors
Tafts Steric Factor

• 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
• Cannot be used for substituents which interact
  with the transition state by resonance or
  hydrogen bonding
• May undervalue the steric effect of groups in an
  intermolecular process (i.e. a drug binding to a
  receptor)

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Steric Factors
Molar Refractivity (MR) - a measure of a
substituents volume
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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

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Hansch Equation

• Conclusions
• Activity increases if p is ve (i.e. hydrophobic
  substituents)
• Activity increases if s is negative (i.e.
  e-donating substituents)

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Hansch Equation
Example Antimalarial activity of phenanthrene
aminocarbinols

• Conclusions
• Activity increases slightly as log P
  (hydrophobicity) increases (note that the
  constant is only 0.14)
• Parabolic equation implies an optimum log Po
  value for activity
• Activity increases for hydrophobic substituents
  (esp. ring Y)
• Activity increases for e-withdrawing substituents
  (esp. ring Y)