QSAR Flashcards
What does QSAR stand for?
Quantitative structure-activity relationship.
Why is QSAR used?
To decide which compounds to make out of a set of compounds with known biological activity.
Does QSAR require any knowledge of the receptor, active site, or the mechanism of action of the compounds?
No.
What is required of the compounds used to build a QSAR equation?
They must all act in the same way against the same receptor or active site.
Outline the general procedure of creating the QSAR equation.
- Select a set of molecules with the same activities on the same receptor.
- Calculate features.
- Divide the set into two subgroups (training and testing).
- Build a model using the training set.
- Test the model on the testing set.
What two sets are the molecules divided into?
Testing and training.
What is the training group used for?
Building the QSAR equation.
What is the testing group used for?
To test the QSAR equation, preventing overfitting.
Outline the steps in the preparation of the structures for QSAR.
- Draw the compounds.
- Clean up the structure by performing a molecular mechanics geometry optimisation.
- Identify key rotatable bonds and perform a conformation search.
- Perform a semi-empirical quantum mechanical geometry optimisation on the lowest energy conformation identified in step 3.
Describe molecular mechanics geometry optimisation.
- Considers atoms as balls with mass and springs with a force constant.
- Does not consider electrons.
- Fast.
- Low quality but okay for a quick clean up of a drawn structure.
Describe semi-empirical quantum mechanical geometry optimisation.
- The valence electrons are used to construct molecular orbitals.
- The inner electrons are approximated via a parameter set (fully calculating would take too long).
- Slower than molecular mechanics but better quality.
Why do energy minimisation techniques tend to find the nearest local minimum in the energy surface?
All energy minimisation techniques concentrate on searching ‘downhill’.
Why is conformational searching prefered over energy minimisation?
Because when energy minimisation is used alone it is not capable of finding the global minimum energy. If a much deeper energy minimum is separated from the current location by an area of greater energy then it won’t be accessible.
Outline conformation searching.
Each rotatable bond is stepped round in small increments and the energies of the resulting conformations are calculated.
This is used to find the approximate position of the global minimum energy well.
After this, a high-quality energy minimisation technique can be used to refine the structure down to the global minimum energy conformation.
What is a conformational explosion?
An increase in rotatable bonds leads to a massive increase in possible conformations.
