q Sar Lecture

8/6/2019 q Sar Lecture

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Quantitative Structure-Activity

Relationships (QSAR)

y Attempts to identify and quantitatephysicochemical properties of a drug in relation to

its biological activity or bindingy Studies hydrophobic, electronic, and steric

properties--either whole molecule or pieces

med chemist draws up an equation that quantifies themed chemist draws up an equation that quantifies therelationship & allows one to predict (to somerelationship & allows one to predict (to someextent) the biological activityextent) the biological activity


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Quantitative Structure-Activity

Relationships (QSAR)

%dv fewer compounds may need to be made

,oweverif compound does not fit the

equation, then chemist knows they need to

modify the equation


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Log P

(partition coefficient)

Hydrophobicity

yP = [drug] in octanol / [drug] in water

Vary log P & see how this affects thebiological activity.

Biological activity normally expressed as

1/C, where C = [drug] required to achieve adefined level of biological activity. The moreThe moreactive drugs require lower concs.active drugs require lower concs.


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Log P

(partition coefficient)Hydrophobicity Plot log 1/C vs. log P

Typically over a small range of log P, e.g. 1-4, astraight line is obtainede.ge.g. log 1/C = 0.75 log P + 2.30. log 1/C = 0.75 log P + 2.30

If graph is extended to very high log P values,then get a parabolic curve. Reasons:

y poorly soluble in aqueous phase y trapped in fat depots more susceptible to metabolism


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Log P: Hydrophobicity


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Log P

Parabolic curveParabolic curve::

log 1/C = - k1 (log P)2 + k2 log P + k3

When P small, dominated by log P term

When P large, log P squared dominates & so

activity decreases


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Log P

Note that one is not always measuring

biological activity, sometimes binding!


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*RELATIVELY FEW DRUGS EXIST WHOSEACTIVITY

IS RELATED TO LOGPALONE!!!

--those that do are the general anesthetics--partition into cell

membranes, & thereby affect membrane structure & nerve

function

--no specific drug-receptor interactions


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Log P Values:U

sesWith these equations for anesthetics (ethers only), it is possible to

predict activity if log P known (doesnt work if structure verydifferent)

ether chloroform halothane

0.98 1.97 2.3

(anesthetic activity increases in same order)

Drugs with Log P values close to 2 should be able to enter the CNSefficiently

e.g. barbiturates have log P values close to 2 also; want to makesure log P value is much lower if you dont want possible CNS

side effects


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Example: decreased CNS side

effects


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P vs.T

P measures drugs overall hydrophobicity & measures

drugs transportability

T measures the hydrophobicity of a specific region on the

drug--hydrophobic bonding to a receptor

substituent hydrophobicity constant,substituent hydrophobicity constant,TT


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T

Possible to calculate the substituenthydrophobicity constant (T)

A measure of how hydrophobic relative to H

Measure P experimentally for a standardcompound with and without a substituent (X).

Use this equation:

Tx = log Px - log PH


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T

Tx = log Px - log PH

H is for standard compound

positive T = substituent more hydrophobic than H

negative T = less hydrophobic than H


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T values for various substituents

on aromatic ringsCH3 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


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T values for various substituents

on aromatic ringsCH3 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 meta-chlorobenzamide

= log P for benzene +T for Cl +T for CONH2

= 2.13 + 0.71 - 1.49 = 1.35= 1.35


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Tables ofT

See Table 2.5

Many tables exist for all sorts of differentstructures.

Note that values will be different when using

different solvent systems.

MOST QSARequations have contribution fromMOST QSARequations have contribution from

eitherP oreitherP orTT or bothor both


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Electronic Effects: The Hammett Constant W

Hammett constant (1940) W

Measure e-withdrawing or e-donating effects (compared to

benzoic acid & how affected its ionization)


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Electronic Effects: The Hammett Constant W

Electron WithdrawingGroups:

Equilibrium shifts

Right & Kx > Kbenzoic

Since Wx = log Kx log Kbenzoic, then W will

be positive .

Wx = log (Kx/Kbenzoic)


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Hammett Constants

Hammett constant takes into account bothtakes into account both resonance andresonance and

inductiveinductive effects; thus, the value depends on whether theeffects; thus, the value depends on whether the

substituent issubstituent ispara or metapara or meta substitutedsubstituted

--ortho not measured due to steric effects

In some positions only inductive effects effect & some

both resonance & inductive effects play a part

aliphatic electronic substituent constants are also available


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Uses

Only one known example where just Hammett

constants effectively predict activity (insecticides,diethyl phenyl phosphates.

These drugs do not have to pass into or through a cell

membrane to have activity).

Log (1/C) = 2.282W 0.348


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Steric Effects

y much harder to quantitate

E

xamples are:y Tafts steric factor (Es) (~1956), an experimental

value based on rate constants

y Molar refractivity (MR)--measure of the volume

occupied by an atom or group--equation includes theMW, density, and the index of refraction--

y Verloop steric parameter--computer program uses

bond angles, van der Waals radii, bond lengths


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Putting it all togetherFor a group of antihistamines,

Log (1/C) = 0.440 Es 2.204

(n=30, s=0.307, r= 0.886)

Log (1/C) = 2.814 W - 0.223

(n=30, s=0.519, r= 0.629)

Log (1/C) = 0.492Es - 0.585 W- 2.445

(n=30, s= .301, r= 0.889)


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Hansch Analysis Proposed that drug action could be divided

into 2 stages: 1) Transport & 2) Binding

Log 1/C = k1P = k2P2 + k3W + k4Es + k5


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Hansch Analysis Look at size and sign for each component of

the equation.

Values of r


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Craig Plots Plots of one parameter against another.

For example, T vs. W

U

sed to quickly decide which analogs tosynthesize if the Hansch equation is known.


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Hansch equationslog 1/C = 1.22T 1.59 W + 7.89

(n=22; s=0.238; r= 0.918

log 1/C = 0.398 T + 1.089 W + 1.03 Es + 4.541(n=9; r= 0.955)

log Cb = 0.765 T = 0.540 T2 + 1.505

log 1/c = 1.78 T 0.12W + 1.674


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