Drug Design: QSAR

Question 0

What is the QSAR approach?

Answer 0

In highs is approach we attempt to derive a mathematical relationship between physicochemical parameters and biological activity in the form of an equation.

Question 1

What is QSAR?

Answer 1

Quantitative structure activity relationships

Question 2

Why are QSAR studies undertaken?

Answer 2

Some physicochemical changes made to a drug can be quantified.

Although SAR studies can be rationalised. the whole process still requires a lot of experience and some luck. There are still many possible analogues that could be made.

Question 3

What is the general QSAR equation?

Answer 3

Biological activity = f{parameters}

Question 4

What can we use the derived equation of QSAR studies for?

Answer 4

Predicting in advance the activity of an unknown compound

Deriving structures which exhibits optimum activity so that the medicinal chemists know which type of analogue to prepare. This will cut down the cost and time taken to develop a drug.

Discovering which drug properties have important roles. This gives us info regarding the nature of the active site of an enzyme/receptor.

Question 5

What is the history of QSAR?

Answer 5

Cornwin Hansch realised that activity of a drug was parabolically dependent on log P in 1964.
This was based in the rationale that drugs needed to be able to partition into cell membranes in order to exhibit activity.

He then came up with two equations: one which described drug partitioning into membranes and the other describing the narcotic effect of barbituates

Question 6

What is log P?

Answer 6

This is the hydrophobicity/lipophilicty of a drug measured by investigating a drugs distribution in an octanol/water mixture.

Log p = concentration of drug in octanol/concentration of drug in water

This experiment models the journey of the drug into biological membranes

Question 7

What does the bar graph of log P and percentage of drugs show us?

Answer 7

That the most successful drugs we tend to use clinically are relatively lipophilic

Question 8

What are the three stages that drug action can be divided into?

Answer 8

1) transport of the drug to its site of action
This depends largely on membrane permeability and the drugs lipophilicity

2) stability of the drug
This depends on the ionisation potential of the drug

3) binding of the drug to the target active site
This depends on the size of the drug and the configuration of the structure.

Question 9

What is the equation of drug action (taking into account the three stages of drug action)

Answer 9

Biological activity = lipophilicity + stability + binding

Question 10

What is an ionisation potential?

Answer 10

The energy required for the removal of one electron (like in oxidation)

Question 11

What is the relationship between ionisation potential and drug stability?

Answer 11

Low ionisation potential means a low energy is required to remove an electron, hence drug is unstable and will break apart.
High ionisation potential means a high amount of energy is required to remove an electron, this may be unfavourable for metabolic reactions, hence also not an ideal drug.

The successful drugs have an IE of 8-10eV

Question 12

What is the effect of substituents?

Answer 12

Electronic effects of a substituent can affect the acidicity/basicity of aromatic compounds,

Question 13

What is the Hammett substitution constant?

Answer 13

Symbol: σ
This is the measure of the electron withdrawing or donating groups of a substituent

This only holds for meta and para substituents

Electron donors have a negative σ
While electron withdrawing groups have a positive σ

This constant considers both resonance and induction

Question 14

What happens to the Hammett constant of a compound if there is more than one substituent?

Answer 14

The σ is summed

Question 15

What should the Hammett constant be for a drug with good activity?

Answer 15

Positive.

Question 16

What do QSAR studies indicate if a parameter of a drug with good activity is absent?

Answer 16

That the parameter is not essential to the action of huge drug e.g. If log P is absent, it indicates the drug does not need to cross any cell membranes.

Thus QSAR studies help us to understand the type of system we are working with

Question 17

What are steric factors important?

Answer 17

The molecular dimensions of a drug must be complimentary to the target active site.

This property is difficult to quantify.v

Question 18

What can the rate of acid catalysed ester hydrolysis be related to?

Answer 18

The steric bulk.

The Taft steric parameter Es is calculated this way.

Question 19

What is the molar refractivity?

Answer 19

The measure of a molecular volume that also takes into account the polarisability of the electron cloud in the molecule. This is now done by docking

Question 20

How can multiple linear regression help in the development of drug molecules?

Answer 20

We can plot a parameter of the drug against biological effect.
The multiple linear regression aims to minimise the sum of the differences.

There are two types: forward stepping and backward stepping regression

Generally at least 5 compounds are required for each descriptor

Question 21

How can biological effect be measured?

Answer 21

This can be EC50, or shrinking of the tumour

Question 22

What is forward stepping regression?

Answer 22

You start by introducing one property (log p, Taft constant etc) with biological effect and try to improve the correlation.
E.g. After adding ionisation potential, does it make the biological effect better or worse, if it is worse, remove the ionisation potential

Question 23

What is backward stepping regression?

Answer 23

Where you sum up all the parameters and remove each property to see if it makes the biological effect better or worse.
If it makes it worse, then you don’t want that property back

Question 24

Can a correlation between two variables be a coincidence?

Answer 24

Yes, so you must be logical about your interpretation

Question 25

What are the main concers with QSAR?

Answer 25

Biological data is only semi quantitative in nature
Calculated molecular descriptors have theoretical errors
This is only useful for structurally related species
Statistical indicators can be manipulated until they show what someone likes (i.e. Quite subjective)
Tests can leave out some of your data to verify the system

Question 26

What kind of science is QSAR better suited for?

Answer 26

Chemical structures

Question 27

Why is QSAR a good method for drug design?

Answer 27

Can concentrate on synthesising analogues we know have good activity

Allows us to predict the properties of analogues before they are tested

We can probe the mechanism of biological action and the nature of the binding site