General Concepts in QSAR for Using the QSAR Application Toolbox Part 2
Basics of QSAR

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Transcript of Basics of QSAR
BackgroundBackground
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
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
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.
QSAR and Drug DesignQSAR and Drug DesignCompounds + biological activity
New compounds with improved biological
activity
QSAR
Advantages Advantages DisadvantagesDisadvantages
Understanding effect of structure on activity
Possible to make predictions
Understand interactions***
Lead optimizationMimic random
synthesis
False correlations may arise
Size of the training set is important
Reliability of features, especially for 3D
Multiple modes of action
How to proceed??How to proceed??
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)
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)
… … 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
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
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)
Use of Log PUse of Log P
ππ substitution substitution constantsconstantsMeasures hydrophobicity of a specific region in the molecule
Substituent hydrophobicity constant
Relative to HEquation:
x = log Px  log PH
ππ values for various values for various substituentssubstituents
CH3 tBu 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
Hammet’s constant, Hammet’s constant, σσMeasures ewithdrawing and e
donating effects, mainly in aromatics
Both resonance and inductive effects considered
Aliphatic esubstitution constants also available
Eg: Insecticide, diethyl phenyl phosphates
log 1/C = 2.282 σ – 0.348
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
c
Esc = Es + 0.306 (n3)
Some common termsSome common terms
Correlation coefficient (r)Number of compounds utilized (n)
Standard Deviation (S)r2
F
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