Basics of QSAR

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Backgroundy First step in Drug Design

Lead

identification y Prior to 1960s SAR studies y Attempt were made to interpret chemical structures y Corwin Hansh s work in 1960 turning point y QSAR was established

What is QSAR??Computerized statistical method y Attempts to quantitate Biological activity to geometrical and chemical characteristics y Certain RULES are laid down for the group of compounds y Substituents can then be optimized y Unique scientific blend of Computer Science, Biology and Chemistryy

Why QSAR??y Consider: Place 10 different groups

at 4 different positions on benzene y No. of compounds to be synthesized = 104 y Solution: Synthesize small no of compounds y Lay down rules and go for QSAR.

QSAR and Drug DesignCompounds + biological activity

QSAR

New compounds with improved biological activity

Advantagesy y y y y

Disadvantagesy y y y

Understanding effect of structure on activity Possible to make predictions Understand interactions*** Lead optimization Mimic 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??

Statistical ConceptsInput: n descriptors P1,..Pn and the value of biological activity (EC50 for example) for m compounds. Cpd1 Cpd2 Cpd m Bio 0.7 3.2 P1 3.7 0.4 P2 ... Pn

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

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

QSAR Parametersy

Hydrophobic ParametersPartition coefficients (log P) Pi substitution constants ( )

y

Electronic ParametersIonization constants (pKa) Sigma substitution constants ( )

y

Steric ParametersTaft s constant (Es) Van der Waal s radii ( )

QSAR Parametersy All above parameters affect

biological activity y Problem due to overlap of parameters y Thus,Describing physical properties : solubility, partition coefficient, Rf values, etc Describing chemical properties : Taft s constant, dipole moment, etc

Log Py Partition coefficient y Vary log P & see how this affects the

biological activity y Biological activity normally expressed as 1/C, where C = [drug] required to achieve a defined level of biological activity y Plot log 1/C vs. log P y Relationship can be Linear or NonLinear

Log Py If linear, equation would be:

log 1/C = a.log P + b y If parabolic, equation would be: log 1/C = a.log P + b(log P)2 + c y Used very efficiently to predict activity of anesthetics (ethers)

Use of Log P

substitution constantsy Measures hydrophobicity of a

specific region in the molecule y Substituent hydrophobicity constant y Relative to H y Equation: Tx = log Px - log PH

values for various substituentsCH3 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 + T for Cl = 2.13 + 0.71 = 2.84

Hammet s constant,Measures e-withdrawing and e-donating effects, mainly in aromatics y Both resonance and inductive effects considered y Aliphatic e-substitution constants also available y Eg: Insecticide, diethyl phenyl phosphates log 1/C = 2.282 0.348y

Taft s constant, EsAn experimental value based on rate constants y Buprenorphine vs Morphine y Equation: log (K/K0) = Es y Hancock s modification: Es to Esc Esc = Es + 0.306 (n-3)y

Some common termsy Correlation coefficient (r) y Number of compounds utilized (n) y Standard Deviation (S) y r2 yF

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