Lecture 6 - QSAR2

Question 1

What is Hansch analysis and the general structure of the Hansch equation?

Answer 1

An attempt to mathematically relate drug activity to the 3 physicochemical parameters, based on an equation
log(1/C) = k1(partition parameter) + k2(electronic parameter) + k3(steric parameter) + k4

Question 2

What are the two stages of drug action as proposed by Hansch, and how do these relate to drug activity?

Answer 2

1. Transport of the drug to the target site (depends on hydrophilicity/hydrophobicity)
2. Binding of the drug to the target site (depends on electronic and steric effects)

Question 3

What are the two possible forms a Hansch equation can be in, and what situations would lead to each of these forms?

Answer 3

If you have only a narrow range of logP values, the equation will be linear
log(1/C) = k1(logP) + k2(sigma) + k3(Es) + k4
If logP spans a large range, the graph will be parabolic and the equation quadratic
log(1/C) = k1(logP)sq + k2(logP) + k3(sigma) + k4(Es) + k5

Question 4

Does a Hansch equation always contain all 3 physicochemical parameters? Why/why not?

Answer 4

No. If a physicochemical parameter does not affect the biological activity it should not be included

Question 5

What is the effect on the physicochemical parameter when

• the hydrophobic parameter increases?
• the Hammett substituent constant increases?
• Tafts steric parameter becomes more negative?

Answer 5

• The substituent has greater hydrophobicity
• The substituent is more electron withdrawing
• The substituent is larger

Question 6

For a compound with which you are changing substituents in multiple positions, how many Hansch equations should be produced?

Answer 6

One for each position that is being changed

Question 7

When changing a substituent, how can you determine if the change in biological activity is due to hydrophobic or steric effects? (Or both?)

Answer 7

Measure the biological activity, hydrophobic parameter and steric parameter for many groups. Find a group that breaks the pattern i.e. has very different hydrophobic and steric parameters. Then test biological activity with this group

Question 8

What is ‘n’ in relationship to the Hansch equation, and what is a reliable value for it?

Answer 8

‘n’ is the number of compounds that have been trialled to determine the equation.
10 or more is normally reliable

Question 9

If you cannot find a substituent that satisfies all the parameters, how do you decide which parameter to prioritise?

Answer 9

The physicochemical parameter with the largest effect on drug activity will have the largest coefficient. This is the most important parameter to satisfy in order to maximise the value of log(1/C)

Question 10

How can two physicochemical parameters of many substituents be visually compared with each other?

Answer 10

Craig Plot

Question 11

Name 3 things that impact the accuracy of a Hansch equation

Answer 11

The number of compounds that have been trialled to determine the equation (n) - should trial substituents from every quadrant of a Craig Plot
The accuracy of the biological data used
The choice of parameter

Question 12

Name 3 things that can be easily visualised from a Craig Plot

Answer 12

Whether there is a relationship between the two parameters (any line of best fit)
Which substituents have positive/negative values for each parameter
Which substituent has the highest/lowest value for each parameter

Question 13

Name two reasons why a Hansch analysis might not be possible

Answer 13

Not enough starting materials to make the compounds

The compounds are too complicated to make

Question 14

What is the Topliss decision tree?

Answer 14

An alternative method for deciding what alterations to make to the lead compound for optimisation
Tells you what substituent to add and what position
The next step depends on whether there was more, equal or less biological activity

Question 15

What is the first step in the aromatic ring Topliss decision tree and why?

Answer 15

Add a chlorine atom to the para position (to make 4-Cl)
Chlorine used because adds slight hydrophobicity, with minimal electronic and steric effects (although admittedly it is slightly electron withdrawing)
Para position because has the least impacts on electronic effects

Question 16

What is the second step in the aromatic ring Topliss decision tree, if the addition of chlorine increased biological activity?

Answer 16

Add another chlorine, this time in the meta position (to make 3,4-Cl2)

Question 17

What is the second step in the aromatic ring Topliss decision tree, if the addition of chlorine decreased biological activity?

Answer 17

Replace the chlorine group with an OMe group (4-OMe), as this is electron donating. This will test if the chlorine was bad for activity due to its hydrophobicity or electronic withdrawing effects

Question 18

What is the second step in the aromatic ring Topliss decision tree, if the addition of chlorine did not affect biological activity?

Answer 18

Replace the chlorine with a methyl group (4-CH3) (still in the para position), as instead of being weakly electron withdrawing, this is a weakly electron donating group

Question 19

What is the first step in the aliphatic chain Topliss decision tree and why?

Answer 19

Assuming you start with a methyl substituent:

Replace this with an isopropyl group, as this increases hydrophobicity

Question 20

What is the second step in the aliphatic chain Topliss decision tree, if the addition of isopropyl increased biological activity?

Answer 20

Replace with a cyclic alkyl group as this increases hydrophobicity even further, without impacting the sterics too much

Question 21

What is the second step in the aliphatic chain Topliss decision tree, if the addition of isopropyl decreased biological activity?

Answer 21

Instead try a hydrophilic substituent such as H

Question 22

What is the second step in the aliphatic chain Topliss decision tree, if the addition of isopropyl doesn’t change biological activity?

Answer 22

Try an ethyl group instead

Question 23

What is the main difference between the aromatic ring Topliss decision tree and the aliphatic chain Topliss decision tree?

Answer 23

The aliphatic chain tree doesn’t aim to alter steric effects.
Therefore if the first change (methyl to isopropyl) changes the sterics of the compound, you can’t go any further with this schematic

Question 24

Describe how bioisosteres can be used to optimise a compound following Hansch analysis

Answer 24

If you know that electronic effects is the most important parameter, swap around compounds that are electronic isosteres to alter other parameters without affecting electronics

Question 25

Is the Craig plot or Topliss scheme more preferable?

Answer 25

Craig plot - only use Topliss is this is unavailable