Choosing a Target and Finding Hit/Lead Compounds

Question 1

What is a drug target?

Answer 1

A biomacromolecule (e.g., protein, DNA/RNA) that a drug binds to for therapeutic effect.

Question 2

What factors influence target selection?

Answer 2

1. Disease relevance 2. Market need 3. Target specificity/selectivity 4. Target location in the body 5. Multi-target approaches.

Question 3

What are multi-target drugs?

Answer 3

Drugs designed to interact with multiple targets (e.g., cancer or HIV treatments).

Question 4

What is target validation?

Answer 4

Experimental confirmation that modulating the target affects the disease

Question 5

What is a bioassay?

Answer 5

A test system to measure drug-target interaction and biological activity.

Question 6

What are the two main types of bioassays?

Answer 6

1. In vitro (cell/tissue-based) 2. In vivo (animal models).

Question 7

Why use bacteria or yeast in bioassays?

Answer 7

They can express human proteins like enzymes for drug screening (e.g., HIV protease).

Question 8

What are the limitations of in vivo bioassays?

Answer 8

Expensive, slow, species variabilityWhat is a hit compound?

Question 9

What is high-throughput screening (HTS)?

Answer 9

Automated testing of thousands of compounds against multiple targets.

Question 10

What are false-positive hits in HTS?

Answer 10

Compounds that appear active but interfere non-specifically (e.g., PAINS – Pan-assay interference compounds).

Question 11

What is NMR screening?

Answer 11

Uses NMR spectroscopy to detect compound-protein binding by comparing spectral shifts.

Question 12

What is the advantage of NMR screening over HTS?

Answer 12

Detects weak binding interactions and reduces false positivesWhat are the different sources of hit compounds?

Question 13

What is an example of a microbial-derived drug?

Answer 13

Cephalosporins (from fungi).

Question 14

What are marine sources of drugs?

Answer 14

Corals, sponges, marine bacteria (e.g., marine-derived anticancer compounds).What is the advantage of synthetic libraries?

Question 15

What is drug repurposing?

Answer 15

Using existing drugs for new therapeutic targets.

Question 16

How are natural ligands used in drug design?

Answer 16

As a template to design agonists (activators) or antagonists (blockers).

Question 17

What is an example of an enzyme inhibitor derived from natural substrates?

Answer 17

HIV protease inhibitorsWhat is serendipity in drug discovery?

Question 18

What is an example of a drug discovered by serendipity?

Answer 18

Propranolol (beta-blocker).What is the role of CADD in drug discovery?

Question 19

What are the main types of CADD?

Answer 19

1. Structure-based design 2. Ligand-based design.What does structure-based drug design rely on?

Question 20

What is molecular docking?

Answer 20

A method to predict how a drug binds to its target.What is ligand-based virtual screening?

Question 21

What is a pharmacophore model?

Answer 21

A 3D map of essential functional groups needed for drug activityWhat is fragment-based drug discovery?

Question 22

What rule do fragments in fragment-based drug discovery follow?

Answer 22

Rule of 3: MW <300, ≤3 H-bond donors/acceptors, ClogP ≤3.What is a lead compound?

Question 23

What is lead optimization?

Answer 23

Modifying the structure of a lead compound to improve efficacy, selectivity, and pharmacokinetics.

Question 24

What properties are optimized during lead optimization?

Answer 24

1. Binding affinity 2. Selectivity 3. Solubility 4. Stability 5. Toxicity 6. Bioavailability.What is SAR (Structure-Activity Relationship)?

Question 25

Why is SAR important in drug design?

Answer 25

It helps identify key functional groups necessary for activity and allows rational modifications.

Question 26

What happens if a key functional group is removed?

Answer 26

It may lead to a loss or reduction in biological activity.

Question 27

What types of modifications are made in SAR studies?

Answer 27

1. Adding/removing functional groups 2. Changing ring systems 3. Modifying stereochemistry 4. Introducing bioisosteresWhat are bioisosteres?

Question 28

Why are bioisosteres used in drug design?

Answer 28

To improve potency, reduce toxicity, enhance bioavailability, or avoid metabolism.

Question 29

Give an example of classical bioisosteres.

Answer 29

Replacing -OH with -NH2 or -F to improve stability.

Question 30

Give an example of non-classical bioisosteres.

Answer 30

Replacing a benzene ring with a thiophene ring to reduce metabolismWhat are the key pharmacokinetic properties optimized in lead compounds?

Question 31

What is Lipinski’s Rule of Five?

Answer 31

A set of guidelines predicting oral bioavailability based on: MW <500, logP <5, ≤5 H-bond donors, ≤10 H-bond acceptors.

Question 32

What happens if a drug violates Lipinski’s rules?

Answer 32

It may have poor oral bioavailability.What is a prodrug?

Question 33

Why are prodrugs used?

Answer 33

To improve absorption, reduce side effects, or enhance targeting.

Question 34

Give an example of a prodrug.

Answer 34

Aspirin (converted into salicylic acid)What are common types of drug toxicity?

Question 35

What is a therapeutic index (TI)?

Answer 35

A ratio comparing toxic dose (TD50) to effective dose (ED50). Higher TI = safer drug.

Question 36

Why are hERG (human Ether-à-go-go-Related Gene) channels important in drug safety?

Answer 36

Blocking hERG channels can cause fatal cardiac arrhythmiasWhat is CADD (Computer-Aided Drug Design)?

Question 37

What are the two main approaches in CADD?

Answer 37

1. Structure-based design (molecular docking) 2. Ligand-based design (similarity screening).

Question 38

What is molecular docking?

Answer 38

Predicting how a drug binds to a target protein using software.

Question 39

What is high-throughput screening (HTS)?

Answer 39

A technique that rapidly tests thousands of compounds for biological activity.

Question 40

What are the limitations of HTS?

Answer 40

1. High cost 2. False positives 3. Low hit rateWhat is fragment-based drug discovery?

Question 41

Why are small fragments used?

Answer 41

They explore chemical space more efficiently than large molecules.What is virtual screening?

Question 42

What are the two main types of virtual screening?

Answer 42

1. Ligand-based (similarity search) 2. Structure-based (docking).What is an example of a successful lead optimization?

Question 43

How was imatinib (Gleevec) discovered?

Answer 43

Through rational drug design targeting BCR-ABL kinase in leukemia