Drug Design: Docking And Virtual Screening Flashcards
Why is docking used?
Often there is not enough experimental data to lean on.
We can use an alogarithm which changes the configuration in the binding pocket to see the lowest energy
Why is the binding coefficient important in docking and virtual screening?
We want a drug that binds effectively
Mostly by H bond interactions
Also, entropy is a very difficult derived logarithm. There are problems of using entropy to describe Gibbs free energy
What does docking require?
Crystal structure and something with fitness structure to capture the Gibbs free energy
We want to check our work by linking it to experimental data to confirm that our theoretical work makes sense
What are the practical issues with docking and virtual screening?
Crystal structures
Binding site/pocket
Species
What are the practical issues with crystal structures?
Should ideally have a higher resolution of <1 angstrom
H bonds are not usually seen as H only has 1 electron (crystallography measures electrons density which is very low for H so this has to be added on later)
There are flaws and mistakes in crystal structure
It is rigid altho in reality it is not always the case as proteins are quite dynamic but are assumed to be frozen for simplicity.
Crystalline water molecules are represent
What are the practical issues regarding the binding/side pocket?
Co-crystallised ligand
Intuition/guess work
Requires Specialised alogrithsm
What are the practical issues concerning species?
Homo sapiens not always available so we have to use yeast
Homology modelling- if there is no crystallography data available, we have to take the structure of a related protein with crystallography and superimpose the amino acid sequence
What are the three points regarding ligand binding?
- common view that Ligand hydrophobicity gives affinity, while hydrogen bonding gives specificity
- generally accepted that high affinity ligands bind in low energy conformations
- biochemical systems exhibit enthalpy entropy compensation where increased binding is offset by entropic penalty, and reducing the magnitude of this change is affinity.
Why is critical thinking important?
If a critical attitude is not present, due to the result of modern commercial modelling systems, which always provide a result, the evaluation is at liberty of the user.
What is aurora 2?
A kinase linked to anti cancer properties
What does the example of adenosine reduced into auroroa 2 show?
The software used to generate the green structure is reliable.
What can be used to hypothesise binding series?
Removal of a hydrogen bond showing significantly reduced binding
What is virtual high throughput screening?
A method of finding peak/new compounds without physically screening
How can prediction power of VHTS be improved?
By selecting a good software with
Scientific robustness
User friendliness
Offered at a good price
Why is VHTS used?
It is more cost effective than testing 200,000 compounds experimentally.
It involves calculating a ΔG for all of the docked binding sites
What are the prerequisites for VHTS ?
Virtual compound collections Crystal structures Computational power - CPU Elimination process - screening Experimental verification - assays
What are the different computational methods which can be used in VHTS ?
Crystal structures - protein data bank
ZINC compound collection ~1.2x10^6
GOLD docking alogrithm including goldscore and chemscore
QikProp - used to calculate the molecular descriptors
Nb: there are different fitness functions in each package
What does GOLDscore stand for?
Genetic observational L docking
What is the virtual screening funnel which virtual hit candidates are selected from?
At the top: docked - ranked compounds Consensus scoring LogP/logs filter Toxicology, promiscuous filter Re-docked Visual inspection Virtual hits
What is consensus scoring?
Whee compounds are only taken if the fit in with both the chemscore and goldscore software filters
What is the logP/s filter?
Where we get rid of anything not water soluble
What is the purpose of the tox - promiscuous filter?
Toxic and promiscuous moieties are thrown out
Why was phospholipase C - γ rejected?
Only 25% of it was active. We are generally only interested in relatively potent compounds
What are the advantages of VHTS compared to convention HTS?
You can generate lots of hits but still have nothing with biological activity e,g, project A
You can generate even more hits to find a few progress able series e.g. Phospholipase C γ
You can screen lots of compounds giving 2 real hit series e.g. His tone methyl transferase
