Title: Quantitative StructureActivity Relationships QSAR
1Quantitative Structure-Activity Relationships
(QSAR)
- Attempts to identify and quantitate
physicochemical properties of a drug in relation
to its biological activity or binding - Studies hydrophobic, electronic, and steric
properties--either whole molecule or pieces - med chemist draws up an equation that quantifies
the relationship allows one to predict (to
some extent) the biological activity -
2Quantitative Structure-Activity Relationships
(QSAR)
- Adv fewer compounds may need to be made
- However, if compound does not fit the equation,
then chemist knows they need to modify the
equation -
3Log P (partition coefficient) Hydrophobicity
- P drug in octanol / drug in water
- Vary 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. The more active
drugs require lower concs.
4Log P (partition coefficient) Hydrophobicity
- Plot log 1/C vs. log P
-
- Typically over a small range of log P, e.g. 1-4,
a straight line is obtained - e.g. 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 - poorly soluble in aqueous phase
- trapped in fat depots
- more susceptible to metabolism
5Log P Hydrophobicity
6Log P
- Parabolic 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
7Log P
Note that one is not always measuring biological
activity, sometimes binding!
8RELATIVELY FEW DRUGS EXIST WHOSE ACTIVITY IS
RELATED TO LOG P ALONE!!! --those that do are the
general anesthetics--partition into cell
membranes, thereby affect membrane structure
nerve function --no specific drug-receptor
interactions
9Log P Values Uses
With these equations for anesthetics (ethers
only), it is possible to predict activity if log
P known (doesnt work if structure very
different) 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 CNS efficiently e.g.
barbiturates have log P values close to 2 also
want to make sure log P value is much lower if
you dont want possible CNS side effects
10Example decreased CNS side effects
11P vs. p
-
- P measures drugs overall hydrophobicity
measures drugs transportability - measures the hydrophobicity of a specific region
on the drug--hydrophobic bonding to a receptor - substituent hydrophobicity constant, p
12p
- Possible to calculate the substituent
hydrophobicity constant (p) - A measure of how hydrophobic relative to H
- Measure P experimentally for a standard compound
with and without a substituent (X). Use this
equation -
- px log Px - log PH
13p
- px log Px - log PH
- H is for standard compound
- positive p substituent more hydrophobic than H
- negative p less hydrophobic than H
14p values for various substituents on aromatic
rings
Theoretical Log P for chlorobenzene log P
for benzene p for Cl 2.13 0.71 2.84
15p values for various substituents on aromatic
rings
Theoretical Log P for meta-chlorobenzamide log
P for benzene p for Cl p for CONH2 2.13
0.71 - 1.49 1.35
16Tables of p
- See Table 2.5
- Many tables exist for all sorts of different
structures. - Note that values will be different when using
different solvent systems. - MOST QSAR equations have contribution from either
P or p or both
17Electronic Effects The Hammett Constant s
Hammett constant (1940) s Measure e-withdrawing
or e-donating effects (compared to benzoic acid
how affected its ionization)
18Electronic Effects The Hammett Constant s
Electron Withdrawing Groups Equilibrium shifts
Right Kx gt Kbenzoic Since sx log Kx log
Kbenzoic, then s will be positive . sx log
(Kx/Kbenzoic)
19Electronic Effects The Hammett Constant s
e-withdrawing groups stabilize the
carboxylate ion larger Kx, and have positive s
values e.g. Cl, CN, CF3 e-donating groups (e.g.
alkyl) equilibrium shifts left (favoring
unprotonated) lower Kx and negative s values
20Hammett Constants
Hammett constant takes into account both
resonance and inductive effects thus, the value
depends on whether the substituent is para or
meta substituted --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
21Uses
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) 2.282 s
0.348
22Steric Effects
much harder to quantitate Examples
are Tafts steric factor (Es)
(1956), an experimental value based on rate
constants Molar refractivity
(MR)--measure of the volume occupied by an atom
or group--equation includes the MW, density, and
the index of refraction-- Verloop steric
parameter--computer program uses bond angles, van
der Waals radii, bond lengths
23Putting it all together
- For a group of antihistamines,
- Log (1/C) 0.440 Es 2.204
- (n30, s0.307, r 0.886)
- Log (1/C) 2.814 s - 0.223
- (n30, s0.519, r 0.629)
- Log (1/C) 0.492 Es - 0.585 s - 2.445
- (n30, s .301, r 0.889)
24Hansch Analysis
- Proposed that drug action could be divided into 2
stages 1) Transport 2) Binding - Log 1/C k1P k2P2 k3s k4Es k5
25Hansch Analysis
- Look at size and sign for each component of the
equation. - Values of r ltlt0.9 indicate equation not reliable
- Accuracy depends on using enough analogs,
accuracy of data, choice of parameters.
26Craig Plots
- Plots of one parameter against another.
- For example, p vs. s
- Used to quickly decide which analogs to
synthesize if the Hansch equation is known.
27Hansch equations
log 1/C 1.22 p 1.59 s 7.89 (n22
s0.238 r 0.918 log 1/C 0.398 p 1.089 s
1.03 Es 4.541 (n9 r 0.955) log Cb 0.765
p 0.540 p 2 1.505 log 1/c 1.78 p 0.12 s
1.674
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