drug discovery 2

Question 1

what does rational design mean?

Answer 1

Rational drug design refers to designing drug molecules that bind to a target (e.g. protein, nucleic acid).
It relies on prior knowledge of the structure, function, and mechanism of the target, thereby avoiding random testing of thousands of molecules.

Question 2

What prerequisites are required to use rational design as an approach to drug design?

Answer 2

Structural data either for the target (1 mark) or a closely related biomolecule (1 mark)

Question 3

what is extensive screening?

Give example:

Answer 3

A new chemical entity which is screened against a variety of biological targets.

Lithium

Question 4

what is random screening?

Answer 4

lots of compounds are screened against a fixed therapeutic target.

Question 5

what is semi synthetic route

Answer 5

Synthetically modifying a natural product to produce a final drug molecule

• starting material
• extracted from natural source
• then chemically modify it to give us final product
  A: reduce production cost

Question 6

what is protecting group chemistry

Answer 6

protect reactive functional group from unwanted reactions

-makes sure the reaction occurs at the right places by adding a protecting group

Question 7

A chemist has designed a new class of compound and wants to find out if it has any therapeutic value. Would extensive screening or random screening be the most appropriate choice and why? (2 marks)

Answer 7

Extensive screening as this will allow chemist to screen their compound against lots of targets

Question 8

what is high throughput screening?

Answer 8

Since the arrival of robotics, the screenings (random and extensive) have been combined so as to allow thousands of compounds to be tested against ca. 30 - 50 biological targets per week (or a LOT more!)

Question 9

Explain why combinatorial synthesis is more suited to generating feedstock compounds for high throughput screening than traditional synthesis

Answer 9

Allows you to produce a large number of compounds in one reaction
This is much quicker than producing the compounds one at a time

Question 10

what is the problem with throughput screening

Answer 10

The problem is how to feed these high throughput screens

Natural Products Fairly Slow

Traditional Synthesis (including synthetic intermediates) Fairly Slow

Company libraries of compounds ca. 200 000 compounds

Combinatorial and parallel synthesis methods Potentially millions of compounds

Question 11

How is it possible for combinatorial chemistry to generate such a vast number of compounds?

Answer 11

Traditional synthesis: preparing each compound individually then purifying and characterising it

Combinatorial synthesis: prepare molecules in every combination in the same reaction pot

Uses very reliable reactions to minimize side products and find ways of identifying an active compound from such mixtures

Question 12

what is Traditional synthesis?

Answer 12

preparing each compound individually then purifying and characterising it

Question 13

what is the limitations for combinatorial chemistry

Answer 13

Limitation: Compounds produced have limited structural diversity (all variants of each other)

Question 14

what are the advantages of combinatorial chemistry

Answer 14

Main advantages:
1. Different starting materials can be linked to separate beads, meaning that all the beads can be exposed to the same reagent at the same time

2. Since starting materials and products are bound to a solid support, excess reagents or unbound by-products can easily be removed by washing the resin - this means excess reagents can be used
3. Intermediates in a reaction sequence are bound to the bead and do not need to be purified

In practice, combinatorial libraries are made using ‘solid phase’ techniques.
Starting reagent is attached to a solid ‘bead’ also known as a polymer support (looks like sand)
The reactive group of the polymer is drawn out in full, but linked to a ‘sphere’ which represents the rest of the polymer support.

Question 15

The mixtures of compounds that are separated from the solid support are then ‘identified’ by what technique ?

Answer 15

The mixtures of compounds that are separated from the solid support are then ‘identified’ by a series of deconvolution techniques (e.g. LCMS - Liquid Chromatography Mass Spectrometry).

Question 16

For drug-target binding, a molecule must have:

Answer 16

Correct groups

Correct position

Question 17

how is fragment screening taking place?

Answer 17

Uses a structural technique (typically X-ray crystallography or NMR but MS can also be used)

Relies on SOAKING target with fragments from screen

Whether the fragments bind is determined using STRUCTURAL methods

Lead compounds then produced based on fragment binding - VISUAL MOLECULE OR FRAGMENT

Can be easily combined with computational methods to improve the design of molecules

1. Initial fragment binding - soaking
2. Fragment elongation - increase length to join with another fragment
3. Candidate synthesis

Question 18

what are the three main strategies for fragments?

Answer 18

linking- Two fragments are soaked into a binding site which are then joined together to produce a single compound
growing - systematically increase the size of fragment
merging- too fragments that bind in the same place so you merge them together

Question 19

what is a fragment

Answer 19

8-18 non-H atoms
Follow the rule of 3:
Mass of ca. ≤300
≤3 hydrogen bond donors
≤3 hydrogen bond acceptors
cLogP = 3
On average, number of rotatable bonds ≤3

Question 20

what is pros and cons of fragment based screening

Answer 20

Pros
Systematic approach
Gives access to a far larger section of chemical space than other methods
Rapid via high throughput methods
Combines rational design with high-throughput approach

Cons
Requires structural information
Needs access to high-tech techniques (NMR and X-ray crystallography, expensive)

Question 21

What are the benefits of performing fragment based drug discovery over conventional high-throughput screening?

Answer 21

Gives access to a far larger section of chemical space than other methods Rapid via high throughput methods

Question 22

What are the requirements for using fragment based drug discovery?

Answer 22

Structural data for your target or a closely related biomolecule

Question 23

Could infra-red spectroscopy be used for fragment-based drug design? Justify your answer

Answer 23

No. IR spectroscopy is not a structural technique (1 mark) and cannot tell you how a molecule binds in a binding site (1 mark

Question 24

what is Ethnopharmacology

Answer 24

(study of indigenous medicines)

“The scientific study of substances used medicinally, especially folk remedies, by different ethnic or cultural groups

it was deduced that they had an effect on the central nervous system (CNS) and this was traced to inhibition of the muscarinic acetylcholine receptors

Question 25

Explain how we can discover new uses for potential drug compounds through the clinical observation of side effects

Answer 25

The observation of unanticipated side effects in clinical trials can give very interesting clues for the development of new drugs as the observations are made in human subjects

e.g. The discovery of Cromakalim