Nick (QSAR's)

Question 1

QSAR’s

Answer 1

Quantitative Structure Activity Relationships.
QSAR’s attempts to identify and quantify the physiochemical properties of a drug and to see whether any of these properties influences the drugs biological activity
- Hydrophobicity of the molecule
- Hydrophobicity of substituents
- Electronic properties of substituents
- Steric properties of substituents

When looking at how a particular physiochemical property influences biological activity, the other properties should be kept constant.
Compounds studies should be structurally related and act at the same target and have the same mechanism of action.

Question 2

QSAR summary points

Answer 2

QSAR relates physiochemical properties of a series of drugs to their biological target by means of a mathematical equation.
The common studied physiochemical properties are hydrophobicity, electronic factors and steric factors.

Question 3

Hydrophobicity

Answer 3

The hydrophobic character of a drug is an important property to study in QSAR’s.
The hydrophobic nature is important when considering what factors?:
- absorption through cell membrane
- receptor interaction and binding to target protein
Changing substituents can have a large effect on hydrophobicity

Question 4

Partition coefficients

Answer 4

The hydrophobic character of a drug can be measured using partition coefficients (P).
P = [drug] in octanol/[drug] in water.

Question 5

What does an increase in P indicate

Answer 5

A higher hydrophobicity, more lipophilic molecule. As hydrophobicity increase the activity of the drug increases. The relationship is linear over a narrow range.

Question 6

Concentration

Answer 6

C = concentration of drug needed to achieve desired activity.
The smaller the value of C the more active the drug. Therefore as 1/C increases, the activity of the drug decreases.
LogP^0 = optimum logP.
Optimum values of LogP are between 0 and 3.

The curve can be expressed as an equation (in the form of 0 = ax^2 + bx +c where x is logP):
log(1/C) = -k1(logP)^2 + k2logP + k3
where k1, k2, and k3 are constants. This shows that as logP increases so does log(1/C) but only up to a certain point. Due to the negative sign in the (logP)^2 term, log (1/C) will start to decrease above certain log P values.

Question 7

Why does log(1/C) decrease above a certain log P value?

Answer 7

Once the drug becomes too hydrophobic the drugs may be insoluble in an aqueous media.

Question 8

Anaesthetic activity of ethers

Answer 8

Although the equation varies for different anaesthetics the maximum log P0 value is normally around 2-3.
Most drugs with a logP value close to 2 can enter the CNS (can cross BBB) and is a common cause of CNS side effects.
LogP tells us the slope (the bigger and steeper = more sensitive it is to a changing logP)

Question 9

Hydrophobicity constants

Answer 9

These log P values need to be determined experimentally. Using the concept of hydrophobicity constants allows logP values to be calculated theoretically.
The hydrophobicity constant (π) measures the contribution specific compounds make to the hydrophobicity of the compound relative to hydrogen.
(Adding a CH3 to a benzene ring and looking at the change in hydrophobicity allows you to determine the hydrophobicity constants of different substituents).
Positive π values increase hydrophobicity value of molecule relative to hydrogen.

Question 10

P and π

Answer 10

P measures the importance of a molecule’s overall hydrophobicity (relevant to absorption, binding, etc).
π can help identify specific regions of the molecule that might interact with hydrophobic regions in the binding site.

Question 11

Hydrophobicity summary points

Answer 11

The partition coefficient is a measure of a drugs overall hydrophobicity. Values of logP are used in QSAR equations with larger values indicating greater hydrophobicity.
The substituent hydrophobicity constant is a measure of the hydrophobic character of individual substituents.
The values are different for substituents attached to aliphatic and aromatic systems and are only relevant to the classes of structures from which the values were derived.
Positive values represent substituents more hydrophobic than hydrogen, negative values represent substituents more hydrophilic than hydrogen

Question 12

Electronic effects

Answer 12

Electronic effects will affect the drugs polarity and ionisation.
the drugs polarity and ionisation will influence absorption and binding. It influences how easily it crosses the cell membranes and how it interacts with the binding site.

Question 13

Hammett substitution constant (σ)

Answer 13

Measures the electron withdrawing/donating ability of substituents. It can be measured experimentally and tabulated.
Measure relative to the ionisation of benzoic acid.

Question 14

The equilibrium constant

Answer 14

The equilibrium constant (KH) signifies there are no substituents on the aromatic ring.
KH = [PhCOO-][H+]/[PhCOOH]. (Products/reactants= dissociation constant)
When a substituent is on the ring the equilibrium position is affected. How it is affected depends on whether it is electron donating or withdrawing.

Question 15

What effect will electron withdrawing substituents have on the equilibrium constant?

Answer 15

An electron withdrawing group will make the negative carboxylate group more stable. This shifts the equilibrium to the right which makes the equilibrium constant increase.
(When charge is spread across the molecule the molecule becomes more stable).

Question 16

σX

Answer 16

The Hammett substitution constant (σx) for a particular substituent (X) is given by the following equation:
σX = log(KX/KH)
(KH is equilibrium constant)

Question 17

How will the values of σx for electron withdrawing substituents such as Cl, CN, and CF3 differ to that of electron donating substituents such as Me, Et and t-Bu?

Answer 17

Electron withdrawing groups stabilise the compound so equilibrium shifts to right which means Kx is bigger than KH so σx values are positive.

Question 18

Key points for σ

Answer 18

σ values depend on inductive and resonance effects.
σ value depends on whether the substituent is meta or para.
σ ortho values are invalid due to steric factors. (Intermolecular hydrogen bonding within same molecule- affects ionisation )

Question 19

Nitro groups (NO2)

Answer 19

Positive σ so NO2 has a greater ability to attract electron density compared with hydrogen.
meta nitro group- electronic influence is inductive.
para nitro group- σ is greater which shows that both induction and resonance have an influence in stabilising the negative charge in the ionised form. Para position withdraws electron density more than meta position.

Question 20

Hydroxyl group (OH)

Answer 20

At the meta position σ is 0.12, yet at the para position σ is -0.37. Why?
At the meta position the influence is inductive and electron withdrawing.
At the para position the electron donating influence due to resonance is more significant than the electron withdrawing influence due to induction.

Question 21

QSAR equation for σ

Answer 21

It has been shown for a class of insecticides that activity is related to electronic factors alone.
log(1/C) = 2.282σ - 0.348
This shows that substituents with a positive value for σ will increase activity.

Question 22

Aliphatic electronic substituent values

Answer 22

Aliphatic electronic substituent values can be measured and they are obtained experimentally by measuring the rates of hydrolyses of aliphatic esters.
Hydrolysis- lone pair on O in H2O attacks d+ carbonyl.

Question 23

If X is an electron withdrawing substituent relative to hydrogen, how will the affect the rate of hydrolysis?

Answer 23

The C is d+ so the electron withdrawing group will make this charge more positive so more hydrolysis will occur as it is more readily attacked by nucleophile.

Question 24

Electronic effects summary points

Answer 24

The Hammett substituent constant is a measure of how electron withdrawing or electron donating a substituent is.
It is measured experimentally and is dependant on the relative position of the substituent on the aromatic ring. the value takes into account both inductive and resonance effects.
the inductive effect of substituents on aliphatic molecules can be measured experimentally and tabulated.

Question 25

Steric effects

Answer 25

The shape of a drug will influence how easily it can approach and interact with a binding site

Question 26

Taft steric factor (Es)

Answer 26

The bulk, size and shape of a drug will influence how easily it can approach and interact with a binding site.
Quantifying steric factors are more difficult to quantify. Can be done by comparing the rates o hydrolysis of substituted aliphatic esters against a standard ester under acidic conditions.

Question 27

Steric factor equation

Answer 27

Es = logKx - logK0
Where Kx represents the rate of hydrolysis of an aliphatic ester bearing substituent X and K0 represents the rate of hydrolysis of the reference ester.
K0 is the standard when X is CH3.
If X is a big bulky group it get sin the way of hydrolysis so kX is smaller.

Question 28

Measuring steric factors

Answer 28

There are other methods that have been tried to quantify the steric effects, such as molar refractivity and the Verloop steric parameter. The latter involves measuring the size of substituents using computer software.

Summary: can be measures experimentally or calculated using computer software.