DK - Small Molecule Drug Discovery I Flashcards
(8 cards)
1
Q
Q1: What are the main stages in the drug discovery and development timeline? (5)
A
- Pre-discovery – Basic research to understand disease biology and identify targets.
- Drug discovery & preclinical studies – Find potential therapeutic agents, test in vitro, in vivo, and in silico; assess ADMET and efficacy.
- Clinical trials – Human testing in Phase I (safety), Phase II (efficacy), Phase III (confirmation).
- Review & approval – Regulatory agency analysis of trial data.
- Phase IV – Post-marketing surveillance for long-term safety and effectiveness.
2
Q
Q2: What are the core concepts that guide drug discovery decisions? (6)
A
- Indication – What disease are you targeting?
- Target – What biological component will the drug interact with?
- Modality – What type of treatment is it (e.g., small molecule, biologic, siRNA)?
- Preclinical assay – Assesses target engagement and pharmacology; most drugs fail here.
- Efficacy – How effective is the drug in achieving the desired biological effect?
- Therapeutic window – The dose range where the drug is effective with minimal side effects.
3
Q
Q3: What challenges are involved in aligning target and modality? (3)
A
- Therapeutic efficacy depends on the dose-response relationship of the target to biological outcomes.
- Many effective drugs (e.g. bone marrow transplant, HIV drugs) lack a broad therapeutic window due to toxicity.
4
Q
Q4: What is the assay-efficacy problem in drug development? (2)
A
- Results from lab assays (in vitro) often fail to translate to clinical benefit.
- Natural “experiments” (e.g. CFTR mutation responses, stress in autoimmune models) help define real-world dose-response curves.
5
Q
Q5: What are the key advantages of small molecules in drug development? (7)
A
- Designability – Easy to chemically modify.
- Patentability – Novel structures can be protected as new chemical entities.
- Multipharmacology – Can interact with multiple targets.
- Low production cost – Cheap to make, scalable, often outsourced.
- High bioavailability – Can reach intracellular targets; often orally active.
- Known tox/PK/PD profiles – Extensive clinical experience with small molecules.
- Ease of delivery and compliance – Suitable for diverse patient populations, including elderly and frail.
6
Q
Q6: What are common MOAs by which small molecules act therapeutically? (10)
A
- Enzyme inhibition – Blocks enzymatic function (e.g. atorvastatin, bortezomib).
- Receptor agonism – Activates receptors (e.g. salbutamol, morphine).
- Receptor antagonism – Blocks receptor activation (e.g. losartan, cetirizine).
- Ion channel modulation – Alters ion flow (e.g. ivacaftor, lidocaine).
- Protein-protein interaction (PPI) inhibition – Disrupts critical signaling complexes (e.g. nutlin-3, venetoclax).
- Allosteric modulation – Binds non-active sites to change function (e.g. cinacalcet, maraviroc).
- Targeted protein degradation (PROTACs) – Uses E3 ligase recruitment to degrade targets (e.g. ARV-110, dBET1).
- Nucleic acid interaction – Interferes with DNA/RNA (e.g. doxorubicin, ciprofloxacin).
- Metabolic modulation – Alters metabolic pathways (e.g. methotrexate, rosiglitazone).
- Epigenetic modification – Targets gene regulation machinery (e.g. vorinostat, azacitidine).
7
Q
Q7: What is SAR and why is it critical in drug design? (3)
A
- Structure–Activity Relationship (SAR) explores how molecular structure affects biological activity.
- Helps identify key functional groups essential for target binding and activity.
- SAR informs chemical optimization to improve potency, selectivity, PK, and safety.
8
Q
Q8: What are PK, PD, and PKPD, and how are they evaluated? (3)
A
- PK (Pharmacokinetics): How the drug moves through the body – absorption, distribution, metabolism, excretion.
- PD (Pharmacodynamics): How the drug affects the body – response at various concentrations.
- PKPD: Integrates PK and PD to evaluate response over time and dose, guiding dosing strategies.
