introduction to quantitative structure activity relationships
TRANSCRIPT
Quantitative Structure Activity Relationships
(QSAR)QSAR: Quantifying the relationship between
physicochemical properties and biological activity.
Advantages of QSAR studies:QSAR enables calculation, in advance, what the
biological activity of a novel analog might be, thus cutting down the number of analogs which have to be made. It allows the medicinal chemist some level of prediction.
Disadvantages of QSAR:
1) QSAR studies are only approximative.2) QSAR may be unuseful when many
physicochemical properties are involved since it is not always possible to vary one property without affecting another.
1) Hydrophobic parameters.2) The electronic parameter.3) The steric parameter
The most commonly studied hysicochemical properties:
I- The hydrophobic parameter
Hydrophobicity Penetration to cell membrane
Biologicalactivity
Hydrophobicity Binding to hydrophobic regions
In the receptor
Biologicalactivity
Hydrophobicity Binding to serum albumin
Biologicalactivity
Hydrophobicity Trapping inAdipose tissues
Biologicalactivity
Hydrophobicity Solubility in the bodyAqueous medium
Biologicalactivity
Hydrophobicity Susciptibility toMetabolism and
subsequent elimination
Biologicalactivity
A) Quantifying hydrophobicity of the entire molecule
• The hydrophobicity character of a drug can be expressed by measuring its partition coefficient (P).
• The partition coefficient: the relative distribution of a drug between octanol and water.
partition coefficient (P) = --------------------------
P Hydrophobicity
Concentration of the drug in octanol
Concentration of the drug in water
• In a series of drugs with similar structure, P is measured experimentally for each drug, log P is calculated and plotted against biological activity (log 1/C) to get a graph
• Two types of graphs are possible:a) Straight-line graph.b) Parabolic graph.
a) Straight-line graph:This happens when the drugs tested have a
small range of (log P) values (log P=1-4)
Straight line equationLog (1/C) = K1 log P + K2Once K1 and K2 are determined, we can predict the biological activity
Log (1/C)
Log P
Example:QSAR: Hydrophobicity & binding to serum
albumin• 40 drugs were tested: (P) was measured,
(log P) was calculated and plotted against (log 1/C).
• The following equation was obtained:Log (1/C) = 0.75 log P + 2.3The positive values means a direct relationship
Binding to serum albumin
Hydrophobicity
Binding to serum albumin of a new compound can be predicted by measuring its (P) and applying the equation.
Remarks:• How much a drug binds to serum albumin allows
us to estimate the effective dose of that drug.• A drug exists in blood in equilibrium:Drug bound to serum albumin drug unbound to serum albumin
• When bound to serum albumin, a drug cannot interact with its receptor, therefore, the dose of the drug should be based on the amount of unbound drug in the blood
b) Parabolic graph
• This happens when some of the tested compounds have very high (log P) values.
Parabolic equation:Log(1/C)= -k1 (log P)2 + k2 log P + k3K1, K2 and K3 are constants
• The positive sign in front of log P implies direct relationship in the first part of the graph which is dominated by log P (when P is small).
• The negative sign in front (log P)2 implies inverse relationship in the last part of the graph which is dominated by (log P)2
(when P is large).
Example:QSAR: hydrophobicity of ethers and general
anesthetic activity.The following equation was obtained:Log(1/C)= -0.22 (log P)2 + 1.04 log P + 2.16
Log Po = 2.3• With this equation, it is now possible to predict
the anesthetic activity of other ether structures, given their partition coefficient.
• As a rule of thumb, drugs targeting the CNS should have a log P value of approximately 2.
• It was found that log P value for any class of general anesthetics is around 2.3. This implies that all general anesthetics have the same mechanism of action.
• Problems:1) The log P values for ether, chloroform
and halothane are 0.98, 1.97 and 2.3, respectively. Given log Po = 2.3, rank them in order of increased general anesthetic activity.
2) Drug I (log P = 2.59) is a cardiotonic with CNS side effects while drug II (log P = 1.17) has similar cardiotonic activity with no CNS side effects. How can you explain that ?
N
N
NH
OMe
MeO
N
N
NH
S
MeO
Me
O
I II
B) Quantifying hydrophobicity of a substituent:
The substituent hydrophobicity constant (π):• The hydrophobicity of a substituent can be
expressed by calculating (π).• (π): a measure of how hydrophobic a
substituent is relative to hydrogen.How (π) is calculatuent for a substituent (X) ??1) Partition coefficient are measured
experimentally for a standard compound without a substituent (X).
2) The following equation is applied:πX = log PXp – log PH
Where πX = hydrophobicity of the substituent (X).
PH = Partition coefficient of the standard compoundPx = Partition coefficient of the substituent X
Cl
Benzene
(log P = 2.13
Chlorobenzene
(log P = 2.84
• From several studies, we have now tables hydrophobicity of differrent aromatic and aliphatic substituents.
FBrClCF3OCH3OHt-BuCH3Group
-0.170.600.391.070.47-1.161.680.50πAliphatic
0.140.860.711.16-0.02-0.671.680.52πAromatic
Remarks• The values for aromatic substituents are
different from those of aliphatic ones.• (π) values are only approximative.• (P) is a measure of the overall hydrophobicity of
a drug and therefore it comprises a measure of drug transport across as membranes
• (π) is a measure of the hydrophobicity of a specific substituent in the drug’s skeleton, therefore it is significant only when that substituent is involved in hydrophobic bonding with the receptor.
• In some cases hydrophobicity is significant for example, there is a very little relationship between hydrophobicity of antimalarial drugs and their antimalarial activity. This finding supported the finding that antimalarial act on red blood cells where hydophobicity is not important.
II. Electronic effect
Electronic effect
A) Quantifying the electronic effect of an aromatic substituent:
The Hammett substitution constant (σ):(σ) : a measure of the electron withdrawing or
electron donating ability of an aromatic substituent.
Ionization
Polarity
Tarnsport across cell membrane
Binding to receptor
How (σ) is calculated ??1) Dissociation constant for benzoic acid is
measured experimentally.
COOH COO-
KH = _______________ _______________
COO-
COOH
2) Dissociation constant for benzoic acid substituted with substituent (X) is measured experimentally
.
COOH COO-
X Xelectron withdrawing
group
+ H+
COOH COO-
X Xelectron donating
group
+ H+
The following equation is applied:
σX = log KX – log KH
Remarks:• Electron withdrawing substituents have positive
(σ) values since they stabilize the carboxylate anion and shift the equilibrium to the right. E.g. NO2, Cl, CF3, CN
• Electron donating substituents have negative (σ) values since they destabilize the carboxylate anion and shift the equilibrium to the left. E.g. CH3, CH3CH2, ………
• The Hammett constant takes into account both inductive and mesomeric effect, therefore, the value of (σ) depends on whether the substituent is meta or para.
• (σ) cannot be measured for orthosubstituents steric and electronic effects are strongly overlapped. This is the limitation of Hammett equation.
• The inductive effect operates in all positions while mesomeric effect operates only in the ortho and para not in the meta.
Look at the electronic effect of the hydroxysubstituent:
meta nitro group-electronic effect on R is inductive.
para hydroxy group-electronic influence on R is due to inductive and resonance effect.
Explanation:
Look at the electronic effect of the nitro substituent:
meta nitro group-electronic effect on R is inductive.
para nitro group-electronic influence on R is due to inductive and resonance effect.
OH
ROH
R
O+
R
H O+
R
H O+
R
H
..
-:
-
:-
Examples:
1) In vitro studies drugs operating by a mechanism where cell membrane are not involved. For example, the insecticide diethylphenyl phosphate acts at cholinesterase which exists outside cell membranes.
O P
O
OEt
OEt
XLog(1/C) = 2.282 σ– 0.348
B) Quantifying the electronic effect of an aliphatic substituent:
(σI): a measure of the electron withdrawing or electron donating ability of an aliphatic substituent.
How (σI) is calculated??1) The rate of hydrolysis of methyl acetate is measured
experimentally under basic and acidic conditions.
2) The rate of hydrolysis of methyl acetate having a substituent (X) is measured experimentally.
CH3C
O CH3
O
CH3C
OH
O
+ CH3 OHHydrolysis
X CH2C
O CH3
O
X CH2C
OH
O
+ CH3 OHHydrolysis
(σI) is measured by applying the equation.Remarks:• Only inductive effect is operating in case
of aliphatic substituents.• Electron withdrawing substituents have
positive (σI) values while electron donating substituents have negative (σI) values
Question:To calculate (σI) the rate of hydrolysis of the
ester should be measured under both acidic and basic conditions…. Why ?
Answer: to eliminate the steric factor.Under basic conditions, both steric and
electronic factors are involved.Under acidic conditions only the steric factor
is involved. The steric factor (Es) is eliminated by comparing the rates under both conditions.
III- Steric factors• The bulk, size and shape of drug may
influence its ability to approach the binding site.
• A bulky substituent may hinder the ideal interaction between drug and receptor. Alternatively, a bulky substituent may help to orientate a drug properly for maximum receptor binding.
A) Taft’s steric factor (Es)How (Es) is calculated ??Exactly like the calculation of (σI) but the
rate of hydrolysis of the ester is measured only under acidic conditions. As mentioned before, under acidic conditions only the steric factor (Es) is ivolved.
B) Molar refractivity (MR)(MR): a measure of the volume occupied by an atom or
group of atoms.(MR) is obtained from the following equation:
MR =(n2 - 1)
(n2 + 2)X
MW
d
MW = molecular weight, d = density, n = refractive indexRemarks:MW/d defines the volume.(n2 -1) / (n2 + 2) is a correction factor that defines how
easily substituent can be polarized.
C) Verloop steric Parameter:
• The steric factor is calculated by a computer program called (STERIMOL).
• The program calculate the steric factor using bond lengths, bond angles, van der Waals radii and possible conformation of substituent.
C
O
O
H
B3
B4
L
OOH C
B4 B3
B2
B1
Considering more than one physicochemical property at the same
timeHansch Equation:• Hansch equation relate biological activity
to the most commonly used physicochemical properties.
• If P is limited to a small range, the equation will be linear.
Log (1/C) = k1 log P + k2 σ + k3 Es + k4
Examples:1) Hansch equation for the adrenergic blocking activity for
beta-haloarylamines:Log (1/C) = 1.22 π – 1.59 σ + 7.89
CH CH2 NR1
R2
XY
Analysis of the equation:Activity increases when the substituent has a positive (π)
value (hydrophobic) and a negative (σ) value (electron donating)
2) Hansch equation for the antimalarialactivity of phenanthrene aminocarbinols
Log (1/C) = -0.015 (log P)2 + 0.14 log P + 0.27 Σπx+ 0.40 ΣπY + 0.65 Σ σx + 0.88 Σ σY + 2.34
Analysis of the equation:• Activity increases slightly with increased
hydrophobicity of the molecule (small positive log P).
NR1
R2OH
X
Y
• There is an optimum P value for activity (the equation is parabolic).
• Hydrophobicity of of substituent Y is more important for activity than hydrophobicity of substituent X (0.4 > 0.27).
• Both substituents X and Y should be electron withdrawing (positive values for σx andσY).
• Electron withdrawing ability of substituent Y is more important for activity than electron withdrawing ability of substituent X (0.88 > 0.65)
The Craig Plot:• The Craig plot is a plot of the () values on
the X axis and the () on the Y axis . For example, the Craig plot for para aromatic substituents is shown below;
Advantages of Craig plot:The Craig plot tells us:• Which substituent has positive () and () values.
Which substituents have negative () and () values, which substituents have one positive and one negative values.
• Which substituents have similar () values (ET, Br, CF3). They are interchangeable if () is the principle factor.
• Which substituents have similar () values (COOH, Cl, Br, I).
• Which substituents should be used in QSAR study. Here, analogs should be synthesized with substituents from each quadrant and biological activity tested. Which quadrant is relevant to biological activity is determined. Then we concentrate on substituent from that quadrant.
The Topliss Scheme (Topliss tree).
• There are two Topliss schemes: one for aromatic substituents and another for aliphatic substituents).
• These schemes. Were drawn up by considering the hydrophobicity and the electronic factors of various substituents and are designed such that optimum substituent can be found as efficiently as possible.