QSAR 2

Question 0

Disadvantages of the Hansh approach 7

Answer 0

• descriptors required for substitutents being studied
• new of compounds required (training set)
• limited relevance (of small molecule derived descriptors against drug on biological target)
• partial proton atom of drugs in the body (logD)
• limited to structural class
• extrapolations beyond values limited
• correlation between descriptors

Question 1

Pros of the Hansh approach4

Answer 1

Properties of drug systems can be considered using descriptors derived from small organic molecules
Quick and easy
Predictions are quantitative (can evaluate statistically)
Potential for extrapolation (application to groups not included in the original analysis)

Question 2

To obtain a statistically significant equation how many compounds do we need in our original analysis (training set)?

Answer 2

Five

Question 3

Why do we doubt the relevance of small molecule derived descriptors?

Answer 3

Derived under standard conditions - may not be entirely relevant to biological conditions.

Question 4

Correlations between descriptors is a problem, what does this mean?

Answer 4

Ie charming hydrophobicity of a molecule is likely to be associated with a change in size.

Question 5

Problems with tafts

Answer 5

Measure of intermolecular effect when drugs interact intramolecularly.
As a result Es tents to undervalue the steric effect.

Question 6

Solution to steric effect issues? 2

Answer 6

Alternative ways to quantify steric effect.
1molar refractivity
2verloop steric parameters

Question 7

Molar refractivity…

Answer 7

Qualifies the volume occupies by an atom of group of atoms

Uses density and refractory index

Question 8

Verloop steric parameters

Answer 8

Define the length and radius for substitutents. Based on standard lengthens, van der waals radi and know conformations.
Can be measured for any substitutent.

Question 9

We calculate veerloop with

Answer 9

Sterimol, usually to three sig fig

Question 10

Biological eactivity can be expressed in various different ways. What is RBA?

Answer 10

Relative binding affinity

Question 11

Sigma includes…

Answer 11

Resonance and inductive effects. These can be separated out and in lidded sper earthly in the Hansh equation.

Importance of position on the aromatic ring may also be included.

Question 12

Free Wilson approach

Answer 12

Effects due to unusual groups/specific structural features may be included in terms that represent presence of absence of the group

Question 13

Eg of free Wilson approach

Answer 13

Hydrogen bonding

Question 14

A useful way to refine the equation?

Answer 14

Take into account specified effects at one o more substitutes

Value 1 - group so present
Value 2 - group is absent

Question 15

Disadvantage of putting everything in one equation?

Answer 15

Although such equations give more refined predictions it can be harder to see why a certain group is good or bad for activity.

Question 16

Craig plot usually shows

Answer 16

Sigma v pie, or PI v mr

Question 17

Craig plot

Answer 17

A way of comparing seat of physiochemical properties

helps in planning QSAR studies and choosing analogues.

Question 18

What should you avoid choosing in the Craig plot

Answer 18

Substituents with correlated properties

Question 19

Advantages of Craig 4

Answer 19

Shows at a glance the effects plotted
Easy to see which groups might be interchangeable
Most accurate QSAR equation should have substituents from all four quadrants
Once equation derived new analogues derived form the appropriate quadrant

Question 20

Topliss scheme

Answer 20

A way of applying QSAR to guide synthesis of compounds

One at a time of in small batches, bases on hydrophobic and electronic effects

Question 21

Advantages of topliss 2

Answer 21

Allows choosing substituents based on biological activity of previous members so as to find the optimum as quickly as possible
Usually for minimising no of compounds required (eg if synthetic route is complex and time consuming)

Question 22

3D QSAR

Answer 22

Physiochemical properties are considered for a molecule as a whole, rather than look gift at the individual substituents or fragments.

Question 23

3D QSAR assumes …

Answer 23

Most important features of a molecules are it’s steric field and its electrostatic field, and that biological activity with correlate with these

Question 24

Steric field is…

Electrostatic field is….

Answer 24

Size and shape of the molecule

Electro rich/poor regions in the molecule

Question 25

Advantages of 3d QSAR 5

Answer 25

• no reliance on experimental constants or measurements
• can be applied to models with unusual substituents
• structure of biological target does not need to be known
• provides direction of new molecules for synthesis
• NOT RESTICTED TO SAME STURCTURAL CLASS

Question 26

3d QSAR molecules should…

Answer 26

Interact with binding sites in a similar way

Question 27

CoMFA stands for

Answer 27

Comparative molecular field analytics

Question 28

What happens in CoMFA

Answer 28

Molecules built in modelling software
Active conformation defines and pharmacophore identified
Pharmacophores aligned before calculating steric and electrostatic fields
Graphical result obtained

Question 29

Graphical result of 3d QSAR shows ….

Answer 29

Favourable and unfavourable interactions (steric or electrostatic).
Makes it easier to visualise SAR and potentially new drug compounds .

Question 30

Properties of a good scaffold

Answer 30

1Privileged scaffold
2Various synthetic routs avail to generate different sub patterns, using wide variety of staring materials
3Low MW to allow scope to add substituents
4several variable groups around scaffold to effectively explore space