1 - Drug Discovery

Question 1

Outline the drug discovery process.

Answer 1

Hit finding

Lead discovery

Lead optimisation

Drug development

Question 2

Through what means can Hit molecules be found?

Answer 2

Me-Too approach

Natural sources

Patent busts

Random screening

Rational target based screening

Question 3

What are Lipinski’s Rule of Five?

Answer 3

MW < 500 Da

Clogp < 5

H-bond donors < 5

H-bond acceptors < 10

Question 4

How are natural human agonists often used in drug design?

Answer 4

Natural agonists can be used as leads for antagonists

Natural substrates for enzymes are often used as leads for competitive inhibitors

Question 5

What’re the advantages of natural drug sources?

Answer 5

Nature has ‘pre-selected’ compounds with pharmacological action - faster than a random search

‘Unusual’ structures not obvious to a chemist can be suggested by nature

Question 6

What’re the disadvantages of natural drug sources?

Answer 6

Collecting, separating, purifying and characterising compounds can be slow

Natural compounds are often complex, chirality, causing difficulty in synthesis

Natural sources may be hard to access, unreliable and subject to legal issues (bio-piracy)

Question 7

Whats the issue with ‘conventional synthesis’?

Answer 7

Synthesis in a stepwise manner is slow and time-consuming
- increasing productivity means more people must be employed

Question 8

Whats the importance of preparing analogues to your led compound?

Answer 8

To establish SARs —> QSARs

To improve biological profile

To exemplify patents

Question 9

What’re the benefits of semisynthetic synthesis?

Answer 9

Can be quick

Usually easy to confirm important functional groups in the lead

Question 10

What’re the disadvantages of semisynthetic synthesis?

Answer 10

Other functional groups in lead may interfere

May not be possible if lead is in short supply - natural source

Question 11

What is combinatorial synthesis?

Answer 11

Combichem consists of the automated synthesis of small quantities of large numbers of compounds using solid phase methods

Question 12

What 2 approaches are there to Combichem?

Answer 12

Parallel synthesis

Synthesis of mixtures

Question 13

What is parallel synthesis?

Answer 13

The same reaction is done on a series of reaction vials, with slightly altered reagents for each vial

Each vial therefore contains only 1 product, whose structure is known on the basis of reagents used

Question 14

What is the benefit of parallel synthesis? What is it used for?

Answer 14

It allows for the synthesis of large numbers of analogues, and is used for fine-tuning a lead

Question 15

What is solid phase synthesis?

Answer 15

A resin, often in the form of beads, is used as an inert support for the chemistry being done.

Question 16

Give an example of a common resin used in solid phase synthesis

Answer 16

Question 17

What’re the benefits of using molecular modelling?

Answer 17

Cheaper / more powerful computers

Large increase in the structural data of proteins and enzymes from X-ray / NMR

Huge increase in sequence data - e.g. human genome project, 2024 Nobel prize in Chemistry

Question 18

What is a key idea behind molecular modelling?

Answer 18

Molecular modelling only provides models, not complete answers.

Although it is improving and results are becoming more reliable and accurate

Question 19

What 2 methods are there to modelling in drug design?

Answer 19

1. Structure of target is known
2. Structure of a number of inhibitors is known, but target structure is unknown

Question 20

What methods can be used to determine the structure of proteins/enzymes?

Answer 20

X-ray crystallography

NMR spec

Homology modelling - structure from amino acid sequence (Alphafold2)

Question 21

What’re the benefits of x-ray crystallography?

Answer 21

Gives complete structure of target - 3D

High resolution

Confirms binding mode

Question 22

What’re the limitations of x-ray crystallography?

Answer 22

Large quantities of protein, mg, must be crystallised - can be very difficult

Takes several weeks/months to solve structure

Gives structure in ‘solid phase’, whilst most proteins function in solution

Not successful for receptors as they are not crystalline - transmembrane receptors folding also changes outside of membrane domain

Question 23

What is NMR spectroscopy?

Answer 23

Uses chemical shifts, coupling constants and interatomic interaction to determine structure of protein

Uses Nuclear Overhauser Effect to calculate how close protons are in space

Solves structure in solution - closer to physiological situation

Question 24

What’re the limitations of NMR spectroscopy?

Answer 24

Only applies to relatively small proteins - up to 200 residues

Take a a long time to solve structure as many NMR experiments must be interpreted

Requires mg quantities of protein - LOTS

Question 25

What’re the benefits to homology modelling?

Answer 25

Gene sequencing is very fast
- < 24 hours

Is used to predict the structure of a proteins based on its gene sequence

Question 26

When is homology modelling employed?

Answer 26

Where the sequence of a proteins based with unknown structure shows good homology to a sequence of a protein of known structure

Question 27

What’re the requirements for homology modelling?

Answer 27

Need at least 25% sequence identity

Need at least 50% sequence identity for a ‘good model’

Question 28

What is the accuracy of homology modelling highly dependent on?

Answer 28

Accuracy is highly dependent on finding a good template

Only a viable technique when there is close homology to a protein of known structure

Question 29

What ways can proteins be visualised?

Answer 29

Wire frame

Cartoon / ribbons

Surface

CPK - Corey-Pauling-kolton

Question 30

What is the methodology for non-structure based drug discovery?

Answer 30

When the structures of known ligand and inhibitors are well characterised, certain features of the target structure can be deduced

Relevant 3D oreintation of essential functionalities required for biological activity can be deduced = PHARMACOPHORE

Question 31

What features may be included in the pharmacophore of a pharmacologically active molecule?

Answer 31

H-bonding/accepting

Hydrophobic groups

Aromatic regions

Charged groups

Etc.

Question 32

Why would pharmacophore identification become more difficult?

Answer 32

When a variety of different structural types bind to a common receptor, the pharmacophore becomes less obvious

Question 33

How is the pharmacophore identified computationally?

Answer 33

Molecule which are known to bind are selected

All possible conformations of the molecules and pharmacophore groups are compared to define essential features for binding at the enzyme / receptor

Question 34

What is the general approach to structure based lead optimisation?

Answer 34

Design a flexible structure

Try binding a model - make it less flexible, doe activity increase or decrease

If activity is found, try crystallising/modelling into the target

Try to simplify structures in terms of FGs, rings, chirality etc.

Question 35

What is FBDD?

Answer 35

FBDD is a method used for finding lead compounds.

Fragments are small organic molecules
- low MW

It is based on identifying fragments which bind weakly, and then growing / combining them to produce a lead with higher affinity.