Basics of QSAR


Transcript of Basics of QSAR

Page 1: Basics of QSAR
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First step in Drug Design – Lead identification

Prior to 1960s – SAR studiesAttempt were made to interpret chemical structures

Corwin Hansh’s work in 1960 – turning point

QSAR was established

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What is QSAR??What is QSAR??Computerized statistical methodAttempts to quantitate Biological

activity to geometrical and chemical characteristics

Certain ‘RULES’ are laid down for the group of compounds

Substituents can then be optimizedUnique scientific blend of Computer

Science, Biology and Chemistry

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Why QSAR??Why QSAR??Consider: Place 10 different groups at 4 different positions on benzene

No. of compounds to be synthesized = 104

Solution: Synthesize small no of compounds

Lay down rules and go for QSAR.

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QSAR and Drug DesignQSAR and Drug DesignCompounds + biological activity

New compounds with improved biological



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Advantages Advantages DisadvantagesDisadvantages

Understanding effect of structure on activity

Possible to make predictions

Understand interactions***

Lead optimizationMimic random


False correlations may arise

Size of the training set is important

Reliability of features, especially for 3D

Multiple modes of action

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How to proceed??How to proceed??

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Statistical ConceptsStatistical Concepts

Bio P1 P2 ... Pn

Cpd1 0.7 3.7

Cpd2 3.2 0.4

Cpd m

Input: n descriptors P1,..Pn and the value of biological activity (EC50 for example) for m compounds.

find coefficients C0,C1,...Cn such that:

Biological activity = C0+(C1*P1)+...+(Cn*Pn)

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QSAR Parameters…QSAR Parameters…Hydrophobic Parameters

◦Partition coefficients (log P)◦Pi substitution constants (π)

Electronic Parameters◦Ionization constants (pKa)◦Sigma substitution constants (σ)

Steric Parameters◦Taft’s constant (Es)

◦Van der Waal’s radii (γ)

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… … QSAR ParametersQSAR ParametersAll above parameters affect biological activity

Problem due to overlap of parameters

Thus,◦Describing physical properties : solubility, partition coefficient, Rf values, etc

◦Describing chemical properties : Taft’s constant, dipole moment, etc

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Log PLog PPartition coefficientVary log P & see how this affects the biological activity

Biological activity normally expressed as 1/C, where C = [drug] required to achieve a defined level of biological activity

Plot log 1/C vs. log PRelationship can be Linear or Non- Linear

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Log PLog PIf linear, equation would be:

log 1/C = a.log P + bIf parabolic, equation would be:

log 1/C = a.log P + b(log P)2 + c

Used very efficiently to predict activity of anesthetics (ethers)

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Use of Log PUse of Log P

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ππ substitution substitution constantsconstantsMeasures hydrophobicity of a specific region in the molecule

Substituent hydrophobicity constant

Relative to HEquation:

x = log Px - log PH

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ππ values for various values for various substituentssubstituents

CH3 t-Bu OH CONH2 CF3 Cl Br F

0.52 1.68 -0.67 -1.49 1.16 0.71 0.86 0.14

Theoretical Log P for chlorobenzene

= log P for benzene + for Cl

= 2.13 + 0.71 = 2.84

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Hammet’s constant, Hammet’s constant, σσMeasures e-withdrawing and e-

donating effects, mainly in aromatics

Both resonance and inductive effects considered

Aliphatic e-substitution constants also available

Eg: Insecticide, diethyl phenyl phosphates

log 1/C = 2.282 σ – 0.348

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Taft’s constant, Es Taft’s constant, Es An experimental value based on

rate constantsBuprenorphine vs MorphineEquation:

log (K/K0) = EsHancock’s modification: Es to Es


Esc = Es + 0.306 (n-3)

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Some common termsSome common terms

Correlation coefficient (r)Number of compounds utilized (n)

Standard Deviation (S)r2


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