Drug Design: Docking And Virtual Screening

Question 0

Why is docking used?

Answer 0

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

Question 1

Why is the binding coefficient important in docking and virtual screening?

Answer 1

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

Question 2

What does docking require?

Answer 2

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

Question 3

What are the practical issues with docking and virtual screening?

Answer 3

Crystal structures
Binding site/pocket
Species

Question 4

What are the practical issues with crystal structures?

Answer 4

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

Question 5

What are the practical issues regarding the binding/side pocket?

Answer 5

Co-crystallised ligand
Intuition/guess work
Requires Specialised alogrithsm

Question 6

What are the practical issues concerning species?

Answer 6

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

Question 7

What are the three points regarding ligand binding?

Answer 7

• 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.

Question 8

Why is critical thinking important?

Answer 8

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.

Question 9

What is aurora 2?

Answer 9

A kinase linked to anti cancer properties

Question 10

What does the example of adenosine reduced into auroroa 2 show?

Answer 10

The software used to generate the green structure is reliable.

Question 11

What can be used to hypothesise binding series?

Answer 11

Removal of a hydrogen bond showing significantly reduced binding

Question 12

What is virtual high throughput screening?

Answer 12

A method of finding peak/new compounds without physically screening

Question 13

How can prediction power of VHTS be improved?

Answer 13

By selecting a good software with

Scientific robustness
User friendliness
Offered at a good price

Question 14

Why is VHTS used?

Answer 14

It is more cost effective than testing 200,000 compounds experimentally.
It involves calculating a ΔG for all of the docked binding sites

Question 15

What are the prerequisites for VHTS ?

Answer 15

Virtual compound collections
Crystal structures 
Computational power - CPU
Elimination process - screening
Experimental verification - assays

Question 16

What are the different computational methods which can be used in VHTS ?

Answer 16

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

Question 17

What does GOLDscore stand for?

Answer 17

Genetic observational L docking

Question 18

What is the virtual screening funnel which virtual hit candidates are selected from?

Answer 18

At the top: docked - ranked compounds
Consensus scoring 
LogP/logs filter
Toxicology, promiscuous filter
Re-docked
Visual inspection
Virtual hits

Question 19

What is consensus scoring?

Answer 19

Whee compounds are only taken if the fit in with both the chemscore and goldscore software filters

Question 20

What is the logP/s filter?

Answer 20

Where we get rid of anything not water soluble

Question 21

What is the purpose of the tox - promiscuous filter?

Answer 21

Toxic and promiscuous moieties are thrown out

Question 22

Why was phospholipase C - γ rejected?

Answer 22

Only 25% of it was active. We are generally only interested in relatively potent compounds

Question 23

What are the advantages of VHTS compared to convention HTS?

Answer 23

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

Question 24

Why is VHTS used?

Answer 24

It can produce valuable hit compounds for drug development products

Good complement to conventional screening methods

However there is much improvement for virtual screening

Question 25

How was LSD discovered?

Answer 25

Serendipitously.v
Albert hoffman - chemist noticed the ergot alkaloids excreted from fungi used to control bleeding after childbirth resulted in excitation when given to animals

There was an accidental inhalation of LSD in 1943