Therapeutic Concepts

Question 1

What are the key drivers of drug discovery and development?

Answer 1

• Scientific curiosity and advancement
• Need for new treatments
• Profitability
• Socioeconomic aspects

Question 2

Scientific curiosity and advancement

Answer 2

• Understanding disease biology
• Identifying drug targets
• Advances in screening, genomics, and molecular modelling

Question 3

Need for New Treatments

Answer 3

• Unmet Medical Needs
• Improving Standards of Care
• Addressing resistance to current therapies

Question 4

Profitability

Answer 4

• Blockbuster potential
• Patents and exclusivity
• Pricing and reimbursement environment

Question 5

Socioeconomic aspects

Answer 5

• Global needs
• Neglected diseases

Question 6

Types of macromolecules

Answer 6

• Proteins
• Nucleic acids
• Polysaccharides
• Lipids

Question 7

Importance of 3D structures in drug design

Answer 7

• Information about the molecular basis of disease
• Binding sites
• Protein interactions
• Target flexibility
• Ligand binding and unbinding kinetics

Question 8

Techniques using 3D structures of macromolecules

Answer 8

• Molecular docking
• Structure-based drug design

Use 3D information to optimise drug-target interactions and enhance specificity

Question 9

Disease-associated proteins and pathways

Answer 9

• Cancer is caused by mutations in oncogenes or tumour suppressor genes that regulate cell growth and division.
• Alzheimer’s Disease is linked to the accumulation of beta-amyloid plaques.
• Imatinib: Targets the Bcr-Abl fusion protein involved in the growth of leukaemia cells and is highly effective in treating chronic myeloid leukaemia (CML).

Question 10

Nucleic acid targets

Answer 10

• DNA-targeting drugs work by damaging DNA
• mRNA-targeting drugs work by blocking the production of specific proteins involved in disease
• Doxorubicin (ionically) binds to the DNA backbone and disrupts cell replication

Question 11

Membrane receptors and cell surface proteins

Answer 11

Tiotropium is a bronchodilator that inhibits the interaction between acetylcholine and the muscarinic acetylcholine receptor

Question 12

Needs and opportunities for new therapeutic agents

Answer 12

• Advances in biotechnology
• Existing drugs may have side effects/toxicity
• Need for personalised medicine due to genetics/lifestyle factors
• Investments in R&D drive innovation
• Greater understanding of disease mechanisms
• Drug resistance
• Improved screening methods

Question 13

Socio-economic factors

Answer 13

• Developed countries: This market can afford new drugs and companies can recover the cost of DD—disease examples: migraine, depression, obesity etc.
• Developing countries: Less R&D carried out due to lack of funding

Question 14

Therapeutic effect (definition)

Answer 14

Therapeutic effect is the intended, positive impact a drug has on the body, it is an endpoint clinicians want to achieve by prescribing a particular medication.

Question 15

Concepts influencing therapeutic efficacy

Answer 15

• Efficacy: Tested in clinical trials
• Selectivity: Selective drugs are typically more effective and less toxic than non-selective drugs
• Pharmacokinetics (ADME): How the drug is absorbed, distributed, metabolised, and excreted by the body
• Pharmacodynamics: The molecular, biochemical, and physiological effects of the drug + mechanism of action
• Toxicity: Acute toxicity can be life-threatening, while chronic toxicity can lead to serious health problems, such as organ damage

Question 16

Target identification and validation

Answer 16

• Identification: using genomic, proteomic, and bioinformatics data
• Validation: genetic screens, expression profiling, and functional assays
• Assess druggability: evaluate target binding sites, ligand interactions, assay feasibility
• Prioritisation: based on relevance, tractability, and novelty.

Question 17

Hit and lead compound identification

Answer 17

• High-throughput screening
• Natural products
• Computational virtual screening
• Structure-based DD
• De novo DD
• Fragment-based approaches
• In silico screening

Question 18

High-throughput screening

Answer 18

Automated biochemical or cell-based assays to test large libraries of compounds

Question 19

Natural products

Answer 19

Screening substances from microbes, plants, and animals

Question 20

Computational virtual screening

Answer 20

Docking virtual libraries against a target structure to select candidates. Assessing ADMET early provides data on absorption, distribution, metabolism, excretion, and toxicity.

Question 21

Structure-based drug design

Answer 21

Utilises detailed 3D structural data on the target, often obtained by X-ray crystallography or cryo-EM, allowing for the rational design of complementarily-shaped small molecules to target binding pockets.

Question 22

De novo drug design

Answer 22

Employs computational modelling to create novel compounds predicted to bind with high affinity

Question 23

Fragment-based approaches

Answer 23

Screen low molecular weight fragments that bind weekly on their own but can be linked or grown into potent leads

Question 24

In Silico screening

Answer 24

Virtual docking of molecular libraries against target structures

Question 25

Lead optimisation

Answer 25

• Structure-activity relationship: understanding how modifications to a molecule affect its potency and selectivity
• ADME optimisation: improving the drug’s bioavailability, stability, and half-life, while minimizing toxicity

Question 26

Preclinical studies

Answer 26

• In vivo and in vitro
• Key studies: cell viability, enzyme kinetics, toxicology, pharmacokinetics, and bioavailability

Question 27

Phase I clinical trials

Answer 27

• Safety and pharmacokinetics testing in healthy volunteers (20-100 people).
• ADMEs are characterised to inform appropriate dosing.
• Many drugs fail at this stage due to toxicity or poor pharmacokinetics.
• Typical duration: 1-2 years.

Question 28

Phase II clinical trials

Answer 28

• Efficacy testing in patients (100-500 people)
• Short-term side effects and dosing/timings are assessed
• Does the drug have pharmacological activity in real patients vs. healthy volunteers
• Typical duration: 2-3 years

Question 29

Phase III clinical trials

Answer 29

• Large-scale trials (1000-5000 patients)
• Confirm efficacy and monitor safety by comparing the drug to placebo or standard of care
• Frequently double-blinded, randomised, multiple centres/locations
• Failure can occur due to a lack of efficacy or safety issues
• Typical duration: 2-4 years

Question 30

Post-Approval Monitoring and Pharmacovigilance

Answer 30

• Post-release monitoring for adverse effects.
• Pharmacovigilance to detect rare side effects that may not have been apparent in clinical trials.