Ian Eggleston - Additional QSAR parameters and approaches

Question 1

List 4 advantages of the Hansch approach…

Answer 1

1) Properties of drugs in biological systems considered using descriptors (pie, sigma, Es) derived from small organic molecules
2) Quick and easy (see if struc should have right biological activity)
3) Predictions are quantitative and may be evaluated statistically (see how well fits data)
4) Potential for extrapolation: conclusions may be extended to other cases (other groups) not in original analysis

Question 2

List 7 disadvantages/limitations of the Hansch approach…

Answer 2

1) Need descriptors for substituents being studied (steric Es, Electronic effects pie, hydrophobicity sigma)
2) Need at least 5 compounds per parameter studied to obtain statistically meaningful equation/correlation (training set)
3) Some descriptors derived from small molecules may be of limited relevance when considering how drug interacts with biological target e.g descriptors of steric factors
4) Partial protonation of drugs may occur at physiological pH
5) Predictions are limited to structural class (congeneric series)
6) Extrapolations beyond values of descriptors used are limited
7) Correlation between physical descriptors is likely (e.g change hydrophobicity of substituent likely to be associate with change in size so pie and Es correlated)

Question 3

List an issue with using the Taft factor Es and how it can be overcome

Answer 3

Issue: Measure of intramolecular effect but drugs interact with target in intermolecular manner
- Tens to undervalue steric effect that substituent will have on binding of drug to target

Solution: Two other ways of quantifying steric effects

• Molar refractivity
• Verloop steric parameters

Question 4

What does molar refractivity (MR) relate to?

Answer 4

• Way of estimating steric effects on activity

- Quantifies volume occupied by atom or group of atoms

Question 5

How is molar refractivity calculated?

Answer 5

(n2-1)/(n2+2) * MW/d

n = refractive index
MW = molecular weight 
d = density

Question 6

What does RBA mean in a Hansch equation?

Answer 6

Relative binding affinity

Question 7

What do Verloop steric parameters define?

Answer 7

• Define the length and radius for a substituent.
• Based on standard bond lengths, VDW radii and known possible conformations
• Can be measured for any substituent

Question 8

What are Verloop steric parameters calculated using?

Answer 8

Sterimol - computer software

Question 9

What does L and B mean in relation to Verloop steric parameters?

Answer 9

L = length of substituent
B = Width of substituent at certain position e.g (1) (2) (3)

Question 10

Electronic effects can be separated out and included separately in a Hansch equation. What can they be separated out in to?

Answer 10

1) Inductive effects (F)
2) Resonance effects (R)

Importance of position of substituent on aromatic ring can be included too

Question 11

How do we include other properties in the Hansch equation?

Give an example of an ‘other’ property…

Answer 11

• Assign ‘novel’ substituents an indicator variable
• Value 1 = present and extra factor added
• Value 0 = absent and no extra factor added
• HBD groups
• Specific groups e.g 4-OCO
  etc. ..

Question 12

What is a disadvantage of including other properties in the Hansch equation by assigning indicator values?

Answer 12

• Tells us the overall effect of presence or absence of a certain substituent BUT doesn’t tell us WHY the presence or absence is good or bad

Question 13

What is the function of Craig Plots? (4)

Answer 13

• To help us compare sets of physiochemical properties
• Help to plan initial QSAR studies
• Helps us to pick further analogues
• Helps avoid choosing substituents where properties are correlated

Question 14

What does a positive pie value mean?

Answer 14

• High hydrophobicity

Question 15

What does a positive hammett substituent value (sigma) mean?

Answer 15

• Electron withdrawing

Question 16

What is the Topliss scheme?

Answer 16

• Shortcut approach
• Applies QSAR to guide synth of compounds one at a time or in small batched based on known substituent hydrophobicity (pie) and electronic effects (sigma)
• Decide which substituents to use, based on biological activity of previous members in series
• Find optimum ASAP
• Minimise number of compounds required

Question 17

What is the principle of 3D QSAR?

Answer 17

• 3D physical properties considered for molecule as a whole rather than looking at individual substituents or fragments

Question 18

What does the 3D QSAR approach assume is that most important feature of a molecule?

Answer 18

• Overall size and shape (steric field)

- Electronic properties (electrostatic field) e.g electron rice/electron poor regions of molecule

Question 19

List 5 advantages to using the 3D QSAR approach

Answer 19

1) No reliance on experimental constants or measurements unlike traditional QSAR
2) Can be applied to molecules with unusual substituents
3) Structure of biological target does not need to be known (does with traditional QSAR)
4) Can provide direct indications of new molecules to synthesise
5) Not restricted to molecules of same structural class
- as long as each molecule is considered in active conformation and pharmacophores of each molecule under consideration are properly aligned

Question 20

How is the 3D QSAR technique CoMFA used?

What result is produced?

Answer 20

• Comparative Molecular Field Analysis
• Builds each molecules using modelling software
• Active conformation of each molecule defined and pharmacophore identified
• Pharmacophore used as ref to correctly align structures of all molecules prior to calc electrostatic and steric fields
• Then relate these to biological activity
• Graphical results are obtained showing favourable and unfavourable interactions (steric/electrostatic) as 3D contours around representative molecule
• Can visualise SAR and potentially design new compounds

e.g
blue areas where addition of steric bulk increases activity
red areas where addition of steric bulk decreases activity