Drug Design Intro

Question 0

What are the main causes of death?

Answer 0

Heart 37%
Cancer 22%

Diabetes 2%
Suicide murder 2%
Lung - non cancer 3%
Accidents 5%
Brain 7%

Other 22%

Question 1

What is the drug discovery pathway?

Answer 1

Biological target identified
High throughput screening utilised
Medicinal chemistry testing, drug molecular pharmacokinetic testing,
Confirmation of biological target
Clinical trials

Question 2

What are the main ways of lead compound discovery?

Answer 2

Ethnopharmacology (aspirin from willow bark)
Screening of natural sources (plants, venoms, sea creatures and soil bacteria)
Combinatorial methods + screening (high throughput screening)
Virtual screening for lead structures
Serendipity (penicillin and Viagra)

Question 3

Why do we not use lead compounds as drugs?

Answer 3

Most lead compounds are unsuitable for clinical use due to being

Not active enough
Having serious or undesired side effects
Not easily administered to patients -> not orally active

Question 4

What is the effect of structural changes to a lead compound?

Answer 4

Structural changes can often alter pharmacological action and improve a particular activity or eliminate side effects.

E.g. Salicylic acid isolated from white willow had good painkiller properties but caused internal bleeding. After being structurally changed to salicylic, there were no undesired side effects while retaining the good painkiller property.

Question 5

What does a lead structure provide?

Answer 5

A basis for the design of new drugs

Question 6

What is neighbourhood behaviour?

Answer 6

Where structurally similar molecules tend to have similar properties e.g. Morphine, codeine and heroin

Question 7

What is the correlation of structure with biological activity known as?

Answer 7

The structure activity relationship

Question 8

What happens during an SAR study?

Answer 8

A number of compounds are made which vary slightly from the original and the biological activity of each one determined

Question 9

What is the aim of a SAR study?

Answer 9

To determine which parts of the lead molecule are essential for biological activity and which parts cause undesired side effects

To develop an analogue of the lead co mound that has the best combination of therapeutic properties

Question 10

What was the very first drug discovery programme based on a SAR approach?

Answer 10

The syphilis cure, Salvarsan which was discovered by Paul Ehrlich in 1910.
The lead compound was Atoxyl. This cured syphilis but was toxic. After 606 analogues were made, eventually Salvarsan aka Arsphenamine was made. This cured syphilis and was much less toxic.

Question 11

What is the basis behind the synthesis of analogues for SAR studies?

Answer 11

There is no strategy or rationale behind these synthesis’

Question 12

Where are SAR studies used?

Answer 12

Commonly in the industry and academia

Identification of all new binding groups in the lead compound can lead to discovery of the pharmacophore

Question 13

What is a pharmacophore?

Answer 13

Contains only the relevant groups that interact with a receptor and are responsible for the activity

Question 14

How are SARs used to determine pharmacophores?

Answer 14

Lead structure is identified
Possible drug target binding groups are identified
Synthesis of a series of analogues where only one binding group is removed is created (if the bioactivity is much lower after modification we know that the functional group is important and all analogues must contain it.
All analogues are tested for biological activity
The pharmacophore is identified

Question 15

What are the three different ways potential binding groups can bind to a target?

Answer 15

Hydrogen bonding- important for groups possessing electron deficient hydrogens e.g. OH and NH2 groups

Ionic bonding- important for groups that can form cations or anions in in vivo e.g. NH2 groups

VDW/hydrophobic contacts- important for hydrophobic groups that can lie close to and interact with hydrophobic groups in a target e.g. aromatic rings, double bonds

Question 16

What are the two kinds of assay formats we use and what can we derive from them?

Answer 16

Biochemical assays which are based on the protein/biomolecule. We can determine the inhibition concentration

Cell based essays which can tell us the germination of half inhibition concentration

Question 17

What are the three points regarding drug receptor interactions?

Answer 17

Ligand hydrophobicity gives affinity, hydrogen bonding gives specificity

High affinity ligands bind in low energy conformations

Biochemical systems exhibit enthalpy entropy compensation where increased bonding is offset by an entropic penalty, reducing the magnitude of change is affinity

Question 18

What does the graph correlating between hydrogen bonds and affinity tell us?

Answer 18

There is no strong correlation (points are scattered all over the place)
This shows us that we should not overdo our hydrogen bonds in our drug structures

Question 19

How was penicillin discovered by serendipity?

Answer 19

Alexander Flemming, a medical doctor and bacteriologist found he grew a mould which killed staph aureus.
This was discovered in 1928 but was not found to have clinical use until pharmacologist Howard Florey and biochemist Ernst Chain discovered the clinical potential in 1940