Drug discovery Flashcards
1
Q
What are the stages of drug discovery?
A
- Disease identification
- Target identification
- Target validation
- High throughput screening assay
- HIT identification
- Primary screening assay
- Lead identification
- Lead optimisation
- Animal model
2
Q
What is the drug life cycle?
A
4 stages:
- Research and discovery
- Non clinical (good lab practice)
- Clinical (good clinical practice)
- Post approval
3
Q
Describe the disease identification.
A
- 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?
4
Q
What is a disease?
A
- Absence of health.
- Health: a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.
5
Q
What is Target identification?
A
- 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”.
6
Q
What is Target validation?
A
- Obtain evidence that drugs acting on a specific target can modify the disease process.
- Transgenic animals
- Polymorphisms/ mutations in human disease
- Use of antibodies
7
Q
What does the pre-clinical stage entail?
A
- 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.
8
Q
What is High throughput screening?
A
- 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.
9
Q
What are HTS libraries?
A
- Drug companies store every compound that they synthesise.
- Thus, each company has their own library
10
Q
What is HIT generation?
A
- 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
11
Q
Give an example of a HTS assay.
A
HTRF: Homogenous time-resolved fluorescence.
12
Q
Fluorescence resonance energy transfer (FRET).
A
13
Q
What is a primary screening assay?
A
- 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.
14
Q
What is lead selection/ identification?
A
- Criteria are chosen for lead compound.
- This is close to final drug.
- Best drug from best series of compounds.
15
Q
What is lead optimisation?
A
- 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.
16
Q
What is an animal model?
A
- Drug is tested in animal model of disease.
- Essential that animal model is good representative of disease process.
17
Q
What is toxicity?
A
- Minimum toxic dose determined in mice to confirm suitability of drug.
- Possibility of in vitro toxicology on human cells.
18
Q
What is bio-availability?
A
- 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.
19
Q
What is candidate selection?
A
- Best drug becomes a candidate compound.
- Drug is passed over to Development group.
- Back-up project is then initiated.
20
Q
What is rational drug design?
A
- Understanding receptor-ligand interactions at molecular levels can be used to design new drugs.
- Numerous techniques used.
21
Q
What is QSAR?
A
- 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
22
Q
Example of QSAR?
A
23
Q
Discuss QSAR parameters.
A
- 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.
24
Q
What are QSAR models?
A
- Mathematical models that can be used to predict the physicochemical, biological and environmental fate properties of compounds from the knowledge of their chemical structure.
25
What are other rational methods?
- 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.
26
What is Rational drug design?
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.
27
What is a pharmacophore?
- 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.
28
What are functional groups?
29
What is Lipinski's rule of five?
- 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
30
What is the Rule-of-three for fragments?
- 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.
