Enzyme kinetic 4 Flashcards
What is the aim of molecular docking?
To give a prediction of the ligand-receptor complex structure using computational methods.
What are the disadvantages of High throughput screening?
- Expensive
- Produces false positive
- Takes along time
Name an example of a protein docking programme?
EADocking
Give example of the 1D descriptors required to identify a good inhibitor?
- MWt
- chemical composition
- hydrophobicity
Give example of the 2D descriptors required to identify a good inhibitor?
- Bond order
- degree of branching, flexibility
Give example of the 3D descriptors required to identify a good inhibitor?
- overall charge
- Pharmacore
What is pharmacore?
The spatial arrangement of chemical groups that determine its activity
What is Structure Activity Relationships (SAR)?
The relationship between the chemical or 3D structure of a molecule and its biology activity.
Why do you need to check the biological activity of each compound?
In many cases you do not want long lasting effects, need to know Kon and Koff
What might you do to investigate SAR?
- crystallography
- screening inhibitor and homologues
- modify functional groups, if activity is lowered then the group is important and visa versa
What are Lipinski’s rule of five a rule of thumb for?
Whether a molecule could be a successful at being a drug?
How many Lipinski’s rules of 5’s are there?
4, lololol
What are the Lipinski rules of 5?
1)
How do you calculate LogP?
P = [D]lipid/[D]water
Why are Lipinski’s rule of five names thusly?
All the numbers in the rules are multiple of five
There are no exceptions to the rule of 5. True or False?
False, there many examples
In silico screening is used to identify potential lead compounds from a database. What does this database assign to these compounds? What is it used for?
Scores, rankings and sets of chemical structures.
It is used to pose a prediction.
It is also able to take into account the type of compound you want i.e. hydrophobic. This requires a high resolution structure because you need to exact positions of the side chains to know the chemical state of the binding site.
What are the three general methods of in silico docking?
- Dock compound to active site
- Define active site of protein - build component to fit in active site
- Define binding site to software and also a small part (fragments of substrate)
What is rigid docking?
Docking in which ligand is treated as a rigid structure and only translational and rotational degrees of freedom are considered.
The ligand is presented as sphere centre in rigid or flexible docking?
rigid docking
What is the advantage of rigid docking over flexible docking?
It enables you to search 100-1000s of compounds without much laborious work
What is flexible docking?
Docking in which the substrate is assumed to have some flexibility along torsion angles which allows for side chain rotation but doesn’t allow for big conformational changes.
What is the advantage of flexible docking over rigid docking?
It provides a higher hit rate in terms of identifying possible conformations.
Aside from the process being time consuming what is an issue with flexible docking?
If the protein undergoes large conformational change then the system won’t be able to produce good hits.
ie open and closed states.
