Drug discovery

Question 1

What are the stages of drug discovery?

Answer 1

• Disease identification
• Target identification
• Target validation
• High throughput screening assay
• HIT identification
• Primary screening assay
• Lead identification
• Lead optimisation
• Animal model

Question 2

What is the drug life cycle?

Answer 2

4 stages:
- Research and discovery
- Non clinical (good lab practice)
- Clinical (good clinical practice)
- Post approval

Question 3

Describe the disease identification.

Answer 3

• Identify a disease that requires treatment and how is it define?
• What therapies already exist or problems with existing therapies?
• What are the competitors doing?

Question 4

What is a disease?

Answer 4

• Absence of health.
• Health: a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.

Question 5

What is Target identification?

Answer 5

• Necessary to identify a specific receptor or enzyme involved in a disease.
• Target should be specific to diseased tissue.
• ## Some targets are not “drug-able”.

Question 6

What is Target validation?

Answer 6

• Obtain evidence that drugs acting on a specific target can modify the disease process.
• Transgenic animals
• Polymorphisms/ mutations in human disease
• Use of antibodies

Question 7

What does the pre-clinical stage entail?

Answer 7

• Hit compound: A compound from high-throughput screen with activity on the target.
• Lead compound: The most promising hit compound selected for further work.
• Lead optimisation: Screening of derivatives of lead compound for improved activity.
• Candidate compound: Best compound selected for clinical development.

Question 8

What is High throughput screening?

Answer 8

• Necessary to have assay for drug-target combination.
• Needs to be high throughput
• Between 10,000-1 million compounds will be screened.
• Used in drug discovery to identify hits from compound libraries that may become leads for medicinal chemistry optimisation.
• Cheap, easy, quick and dirty.
• Choose criterion for selection.

Question 9

What are HTS libraries?

Answer 9

• Drug companies store every compound that they synthesise.
• Thus, each company has their own library

Question 10

What is HIT generation?

Answer 10

• Most active compounds from screening are selected as hit compounds.
• Chosen for unique chemical structure
• Potential for derivative synthesis:
  1.Easy chemistry
  2. Few patents

Question 11

Give an example of a HTS assay.

Answer 11

HTRF: Homogenous time-resolved fluorescence.

Question 12

Fluorescence resonance energy transfer (FRET).

Answer 12

Question 13

What is a primary screening assay?

Answer 13

• Hit derivatives are tested in primary screening assay.
• Does not need to be high throughput.
• Needs to be more clinically relevant.
• Dose response curves generated.

Question 14

What is lead selection/ identification?

Answer 14

• Criteria are chosen for lead compound.
• This is close to final drug.
• Best drug from best series of compounds.

Question 15

What is lead optimisation?

Answer 15

• The lead compound is not a drug.
• It is usually the most potent agent discovered.
• To be an effective drug ADME-T factors must also be considered.

Question 16

What is an animal model?

Answer 16

• Drug is tested in animal model of disease.
• Essential that animal model is good representative of disease process.

Question 17

What is toxicity?

Answer 17

• Minimum toxic dose determined in mice to confirm suitability of drug.
• Possibility of in vitro toxicology on human cells.

Question 18

What is bio-availability?

Answer 18

• Drug is tested for oral activity.
• If necessary pro-drug is synthesised.
• Some drugs are very active and meet all criteria except oral activity.
• % of oral drug that reaches the systemic circulation.

Question 19

What is candidate selection?

Answer 19

• Best drug becomes a candidate compound.
• Drug is passed over to Development group.
• Back-up project is then initiated.

Question 20

What is rational drug design?

Answer 20

• Understanding receptor-ligand interactions at molecular levels can be used to design new drugs.
• Numerous techniques used.

Question 21

What is QSAR?

Answer 21

• Quantitative structure-activity relationship
• Requires data from a series of compounds
• Relates features of molecules to activity
  1. Solubility
  2. Electron density
  3. Molecular volume
• Used to predict potential derivatives

Question 22

Example of QSAR?

Answer 22

Question 23

Discuss QSAR parameters.

Answer 23

• A measure of the potential contribution of its group to a particular property of the parent drug.
• MIC: minimum inhibitory concentration against E. coli
• pi, sm, sp, F, R, ES & MR are molecular parameters
• Best models for R1, R6, R7 and R8 established.

Question 24

What are QSAR models?

Answer 24

• Mathematical models that can be used to predict the physicochemical, biological and environmental fate properties of compounds from the knowledge of their chemical structure.

Question 25

What are other rational methods?

Answer 25

• Used if no lead or hit compounds available.
• Other software allows ligand prediction if there is a crystal structure of receptor/enzyme or of a homolog.

Question 26

What is Rational drug design?

Answer 26

1. Swiss-pdb:
   - 3D protein analysis and homology model generation-based on a protein crystal structure.
2. Virtual screening:
   - Docking small ligands into a known 3D protein structure.
   - Usually 10 million + compounds screened
   - Rapid and inexpensive
3. Pharmacophore generation.

Question 27

What is a pharmacophore?

Answer 27

• A theoretical object that summarises the chemical requirements for a compound in 3D.
• It shows where the hydrophobic regions are, where the electron donor/acceptors are.
• One can also include parameters to force the ligand into a specific volume.
• Pharmacophores can be generated based on the pocket of the enzyme, or on the ligand.

Question 28

What are functional groups?

Answer 28

Question 29

What is Lipinski’s rule of five?

Answer 29

• States that an orally active drug has no more than one violation of the following criteria:
  1. No more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
  2. No more than 10 hydrogen bond acceptors (all nitrogen or oxygen atoms).
  3. A molecular mass ≤500 Da
  4. log P (octanol-water partition coefficient ) ≤5

Question 30

What is the Rule-of-three for fragments?

Answer 30

• Criteria proposed to describe fragments suitable for biophysical screening:
  1. molecular mass <300 Da,
  2. ogP≤3,
  3. Hydrogen-bond acceptors ≤3
  4. Hydrogen-bond donors ≤3.