Choosing a Target and Finding Hit/Lead Compounds Flashcards
What is a drug target?
A biomacromolecule (e.g., protein, DNA/RNA) that a drug binds to for therapeutic effect.
What factors influence target selection?
- Disease relevance 2. Market need 3. Target specificity/selectivity 4. Target location in the body 5. Multi-target approaches.
What are multi-target drugs?
Drugs designed to interact with multiple targets (e.g., cancer or HIV treatments).
What is target validation?
Experimental confirmation that modulating the target affects the disease
What is a bioassay?
A test system to measure drug-target interaction and biological activity.
What are the two main types of bioassays?
- In vitro (cell/tissue-based) 2. In vivo (animal models).
Why use bacteria or yeast in bioassays?
They can express human proteins like enzymes for drug screening (e.g., HIV protease).
What are the limitations of in vivo bioassays?
Expensive, slow, species variabilityWhat is a hit compound?
What is high-throughput screening (HTS)?
Automated testing of thousands of compounds against multiple targets.
What are false-positive hits in HTS?
Compounds that appear active but interfere non-specifically (e.g., PAINS – Pan-assay interference compounds).
What is NMR screening?
Uses NMR spectroscopy to detect compound-protein binding by comparing spectral shifts.
What is the advantage of NMR screening over HTS?
Detects weak binding interactions and reduces false positivesWhat are the different sources of hit compounds?
What is an example of a microbial-derived drug?
Cephalosporins (from fungi).
What are marine sources of drugs?
Corals, sponges, marine bacteria (e.g., marine-derived anticancer compounds).What is the advantage of synthetic libraries?
What is drug repurposing?
Using existing drugs for new therapeutic targets.
How are natural ligands used in drug design?
As a template to design agonists (activators) or antagonists (blockers).
What is an example of an enzyme inhibitor derived from natural substrates?
HIV protease inhibitorsWhat is serendipity in drug discovery?
What is an example of a drug discovered by serendipity?
Propranolol (beta-blocker).What is the role of CADD in drug discovery?
What are the main types of CADD?
- Structure-based design 2. Ligand-based design.What does structure-based drug design rely on?
What is molecular docking?
A method to predict how a drug binds to its target.What is ligand-based virtual screening?
What is a pharmacophore model?
A 3D map of essential functional groups needed for drug activityWhat is fragment-based drug discovery?
What rule do fragments in fragment-based drug discovery follow?
Rule of 3: MW <300, ≤3 H-bond donors/acceptors, ClogP ≤3.What is a lead compound?
What is lead optimization?
Modifying the structure of a lead compound to improve efficacy, selectivity, and pharmacokinetics.
What properties are optimized during lead optimization?
- Binding affinity 2. Selectivity 3. Solubility 4. Stability 5. Toxicity 6. Bioavailability.What is SAR (Structure-Activity Relationship)?
Why is SAR important in drug design?
It helps identify key functional groups necessary for activity and allows rational modifications.
What happens if a key functional group is removed?
It may lead to a loss or reduction in biological activity.
What types of modifications are made in SAR studies?
- Adding/removing functional groups 2. Changing ring systems 3. Modifying stereochemistry 4. Introducing bioisosteresWhat are bioisosteres?
Why are bioisosteres used in drug design?
To improve potency, reduce toxicity, enhance bioavailability, or avoid metabolism.
Give an example of classical bioisosteres.
Replacing -OH with -NH2 or -F to improve stability.
Give an example of non-classical bioisosteres.
Replacing a benzene ring with a thiophene ring to reduce metabolismWhat are the key pharmacokinetic properties optimized in lead compounds?
What is Lipinski’s Rule of Five?
A set of guidelines predicting oral bioavailability based on: MW <500, logP <5, ≤5 H-bond donors, ≤10 H-bond acceptors.
What happens if a drug violates Lipinski’s rules?
It may have poor oral bioavailability.What is a prodrug?
Why are prodrugs used?
To improve absorption, reduce side effects, or enhance targeting.
Give an example of a prodrug.
Aspirin (converted into salicylic acid)What are common types of drug toxicity?
What is a therapeutic index (TI)?
A ratio comparing toxic dose (TD50) to effective dose (ED50). Higher TI = safer drug.
Why are hERG (human Ether-à-go-go-Related Gene) channels important in drug safety?
Blocking hERG channels can cause fatal cardiac arrhythmiasWhat is CADD (Computer-Aided Drug Design)?
What are the two main approaches in CADD?
- Structure-based design (molecular docking) 2. Ligand-based design (similarity screening).
What is molecular docking?
Predicting how a drug binds to a target protein using software.
What is high-throughput screening (HTS)?
A technique that rapidly tests thousands of compounds for biological activity.
What are the limitations of HTS?
- High cost 2. False positives 3. Low hit rateWhat is fragment-based drug discovery?
Why are small fragments used?
They explore chemical space more efficiently than large molecules.What is virtual screening?
What are the two main types of virtual screening?
- Ligand-based (similarity search) 2. Structure-based (docking).What is an example of a successful lead optimization?
How was imatinib (Gleevec) discovered?
Through rational drug design targeting BCR-ABL kinase in leukemia
