Life cycle of a drug

Question 1

What are Targets-receptors (4)

Answer 1

1. A biological system (involving a receptor, e.g., a protein molecule, DNA, etc.) that, when selectively perturbed, is expected to have a beneficial effect.
2. Off-target effects: Other “processes/receptors” in the body may be susceptible to being perturbed by the same intervention and causing desired and/or adverse effects.
3. Ideally, the “target” must be present in the diseased state/invader and absent in the host. e.g. haemozoin formation in parasites
4. The ratio between activity and toxicity is termed the therapeutic index.

Question 2

What is Mode of action (1)

Answer 2

The effect on the target that is anticipated will lead to the desired outcome.

Question 3

What are examples of the mode of action (3)

Answer 3

1. Inhibition (of an enzyme)
2. Activation or agonism (of a receptor)
3. Blocking or antagonism (of an ion channel or a receptor).

Question 4

What is biochemistry (1)

Answer 4

Biochemistry: a substance which interferes with or inhibits the physiological action of another. e.g. “LSD is a serotonin antagonist

Question 5

What is Screening (5)

Answer 5

1. In general, The process of separating useful molecules from inactive or harmful ones for that indication
2. In drug discovery: Identifying which compounds possess a property that makes them unlikely to become a drug, e.g. a nitro group
3. This is often done by conducting assays.
4. Virtual screening - toxic “alerts”
5. Undetected pan-assay interference compounds (PAINS) with false-positive activities in assays often propagate through medicinal chemistry programs and compromise their outcomes.

Question 6

What is Assaying (2)

Answer 6

1. The process of examining or analysing drug discovery
2. Conducting the various experiments that will allow us to determine if a compound has properties that make it more/less likely to become a drug

Question 7

What is Efficacy (2)

Answer 7

1. In medicine, efficacy is the capacity for the therapeutic effect of a given intervention to improve the health of a patient eventually.
2. In pharmacology, efficacy (Emax) is the maximum response achievable from an applied or dosed agent, for instance, a small molecule drug.

Question 8

What are the steps of Drug Discovery: Efficacy (4)

Answer 8

1. pick a target/disease and route that can be used
2. decide what kind of approach to take (e.g. small molecules, biological or biotechnology products, proteins, peptides, DNA, sugars etc…)
3. find some hits – molecules
4. identify a candidate drug

Question 9

What is Hit (3)

Answer 9

compound with:

1. Confirmed activity
2. Confirmed structure
3. Confirmed purity

Question 10

What is lead (6)

Answer 10

1. Sets of compounds (with similar chemical structure)
2. Compounds with confirmed activity confirmed structure, and confirmed purity.
3. Have a good set of attractive characteristics: activity at the target, solubility, permeability, pharmacokinetics (ADME)
4. No single compound is good enough: lacking some of the characteristics above or has toxicity.
5. Good/High probability of leading to a drug- the perfection of a discovery
6. Leads are made using semi-synthesis.

Question 11

How does small molecule drug discovery affect pharmacokinetics and safety (6)

Answer 11

1. The focus at the lead optimisation stage is normally on ADMET-e.g. Lipinski’s rule of 5; others available.
2. Ensure that the compound gets to the target site.
3. Modulate delivery route, oral, rectal, skin patch, inhaler etc. Avoid 1st pass metabolism.
4. Making sure it is safe (enough)
5. It depends on the disease that is being targeted.
6. e.g. Anticancer drugs are different from analgesics. Selective Toxicity/ fractional cell kill hypothesis.

Question 12

What is a candidate drug (4)

Answer 12

1. A single compound with properties that are thought to satisfy the criteria for the compound to become a drug
2. Medicine = drug + dosage form.
3. Satisfies all the regulatory requirements to initiate clinical trials
4. Affordability-manufacture at a profit. Ideally, 10p/dose /patient.

Question 13

What is the concept of biological drug discovery (2)

Answer 13

1. Increasingly, drugs in clinical trials and receiving marketing authorisation include biological molecules: vaccines, antibodies, antisense oligonucleotides-Biotech revolution.
2. The drug discovery process has similar stages with additional challenges- the industry solves it with bespoke strategies. QC Issues.

Question 14

How does preclinical development work (7)

Answer 14

Establish:

1. The manufacturing of the product
2. The quality control of the product
3. The pharmacology of the drug (Action)
4. The pharmacokinetics of the drug ADME
5. The toxicology of the drug (Various tests)
6. The well-established scientific strategy of drug discovery – can be approached systematically with a reasonable expectation of success.
7. Discovering the right molecule is both a science and an art and is guided by the experience of the investigators.

Question 15

What do pharmaceutical companies make? (7)

Answer 15

1. Pharmaceuticals
2. Intellectual property
3. Most drugs are protected by patents.
4. Patents provide inventors with the exclusive rights to commercialise their inventions for 20 years from their filing date.
5. Granted by governments
6. Requires an invention that is novel, not obvious (inventive) and useful
7. Drug discovery and development can take several decades and cost billions of dollars-exceptions: COVID-19 vaccines.