QSAR 2 Flashcards
(31 cards)
Disadvantages of the Hansh approach 7
- 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
Pros of the Hansh approach4
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)
To obtain a statistically significant equation how many compounds do we need in our original analysis (training set)?
Five
Why do we doubt the relevance of small molecule derived descriptors?
Derived under standard conditions - may not be entirely relevant to biological conditions.
Correlations between descriptors is a problem, what does this mean?
Ie charming hydrophobicity of a molecule is likely to be associated with a change in size.
Problems with tafts
Measure of intermolecular effect when drugs interact intramolecularly.
As a result Es tents to undervalue the steric effect.
Solution to steric effect issues? 2
Alternative ways to quantify steric effect.
1molar refractivity
2verloop steric parameters
Molar refractivity…
Qualifies the volume occupies by an atom of group of atoms
Uses density and refractory index
Verloop steric parameters
Define the length and radius for substitutents. Based on standard lengthens, van der waals radi and know conformations.
Can be measured for any substitutent.
We calculate veerloop with
Sterimol, usually to three sig fig
Biological eactivity can be expressed in various different ways. What is RBA?
Relative binding affinity
Sigma includes…
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.
Free Wilson approach
Effects due to unusual groups/specific structural features may be included in terms that represent presence of absence of the group
Eg of free Wilson approach
Hydrogen bonding
A useful way to refine the equation?
Take into account specified effects at one o more substitutes
Value 1 - group so present
Value 2 - group is absent
Disadvantage of putting everything in one equation?
Although such equations give more refined predictions it can be harder to see why a certain group is good or bad for activity.
Craig plot usually shows
Sigma v pie, or PI v mr
Craig plot
A way of comparing seat of physiochemical properties
helps in planning QSAR studies and choosing analogues.
What should you avoid choosing in the Craig plot
Substituents with correlated properties
Advantages of Craig 4
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
Topliss scheme
A way of applying QSAR to guide synthesis of compounds
One at a time of in small batches, bases on hydrophobic and electronic effects
Advantages of topliss 2
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)
3D QSAR
Physiochemical properties are considered for a molecule as a whole, rather than look gift at the individual substituents or fragments.
3D QSAR assumes …
Most important features of a molecules are it’s steric field and its electrostatic field, and that biological activity with correlate with these
