Applications of combinatorial chemistry in drug discovery MCQs With Answer

Applications of combinatorial chemistry in drug discovery MCQs With Answer

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Introduction: Combinatorial chemistry in drug discovery uses automated methods to create and screen large compound libraries rapidly, accelerating hit identification and lead optimization. Key techniques include solid-phase synthesis, split-and-mix strategies, diversity-oriented and focused libraries, and DNA-encoded libraries. These approaches support high-throughput screening (HTS), structure–activity relationship (SAR) studies, and faster lead generation while improving chemical diversity and efficiency. Understanding library design, deconvolution methods, and quality control is essential for B. Pharm students aiming to contribute to medicinal chemistry and pharmacology projects. Core keywords: combinatorial chemistry, drug discovery, libraries, solid-phase synthesis, split-and-mix, HTS, SAR, lead optimization. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. What is the primary goal of combinatorial chemistry in drug discovery?

  • To synthesize a single high-purity drug candidate
  • To generate large and diverse chemical libraries quickly
  • To replace clinical trials with automated prediction
  • To design only natural product derivatives

Correct Answer: To generate large and diverse chemical libraries quickly

Q2. Which technique is most commonly associated with solid-phase combinatorial synthesis?

  • Liquid-liquid extraction
  • One-bead-one-compound (OBOC) methodology
  • Homogeneous catalysis in solution
  • Classical recrystallization

Correct Answer: One-bead-one-compound (OBOC) methodology

Q3. What does “split-and-mix” synthesis enable?

  • Sequential purification of every intermediate
  • Synthesis of mixture-based libraries by splitting resin and recombining
  • Exclusive synthesis of single-target inhibitors
  • Direct measurement of ADME properties on resin

Correct Answer: Synthesis of mixture-based libraries by splitting resin and recombining

Q4. Which library type focuses on variations around a single core scaffold?

  • Diversity-oriented library
  • Focused library
  • Random polymer library
  • Natural product extract library

Correct Answer: Focused library

Q5. DNA-encoded libraries (DELs) are primarily used because they:

  • Eliminate the need for any screening
  • Allow pooling and selection of billions of compounds with DNA tags
  • Require each compound to be tested individually in vivo
  • Are incompatible with affinity-based selection

Correct Answer: Allow pooling and selection of billions of compounds with DNA tags

Q6. In combinatorial chemistry, “deconvolution” refers to:

  • Combining multiple hits into a single compound
  • Identifying the active component(s) from a mixture that showed activity
  • Sequencing DNA tags in a DEL
  • Purifying library members by chromatography

Correct Answer: Identifying the active component(s) from a mixture that showed activity

Q7. Which method is commonly used for generating positional scanning libraries?

  • Solid-phase split-and-mix with systematic position variation
  • Direct in vivo screening of crude extracts
  • High-resolution NMR-guided synthesis only
  • Single-step combinatorial coupling without records

Correct Answer: Solid-phase split-and-mix with systematic position variation

Q8. One major advantage of one-bead-one-compound (OBOC) libraries is:

  • Every bead contains a mixture of different compounds
  • Direct screening of individual compounds on beads for binding
  • Beads dissolve during screening making identification impossible
  • Beads only allow small library sizes

Correct Answer: Direct screening of individual compounds on beads for binding

Q9. Which analytical technique is essential for quality control of combinatorial libraries?

  • Mass spectrometry to verify molecular weight and identity
  • Polarimetry for rotamer analysis
  • Visual color inspection of reaction vessels
  • Simple pH paper testing only

Correct Answer: Mass spectrometry to verify molecular weight and identity

Q10. Diversity-oriented synthesis (DOS) aims to:

  • Generate structurally diverse small molecules to explore novel chemotypes
  • Create only peptide-based libraries
  • Restrict libraries to variations of one functional group
  • Maximize similarity to a single known drug

Correct Answer: Generate structurally diverse small molecules to explore novel chemotypes

Q11. High-throughput screening (HTS) of combinatorial libraries primarily measures:

  • Only the solubility of compounds
  • Biological activity against targets using automated assays
  • The taste and odor of candidate compounds
  • Only in vivo pharmacokinetics

Correct Answer: Biological activity against targets using automated assays

Q12. Which property is commonly optimized after identifying hits from combinatorial libraries?

  • Room temperature melting point only
  • Lead optimization for potency, selectivity, and ADME
  • Only the synthetic route without bioassays
  • Replacement of all heteroatoms with carbon

Correct Answer: Lead optimization for potency, selectivity, and ADME

Q13. Mixture-based libraries allow rapid screening because:

  • Each assay tests thousands of compounds simultaneously in defined mixtures
  • They eliminate the need for controls
  • They require no follow-up deconvolution
  • They always give single-compound readouts

Correct Answer: Each assay tests thousands of compounds simultaneously in defined mixtures

Q14. Which is a common encoding strategy for tracking combinatorial synthesis?

  • Physical labels or DNA tags attached to compounds
  • Relying on color change of resin only
  • Using random verbal descriptions
  • Not recording any synthesis steps

Correct Answer: Physical labels or DNA tags attached to compounds

Q15. What is a major limitation of very large combinatorial libraries?

  • Unlimited resources ensure no limitations exist
  • Difficulties in storage, screening logistics, and follow-up validation
  • They always give high-quality drug candidates without optimization
  • They render all lead optimization unnecessary

Correct Answer: Difficulties in storage, screening logistics, and follow-up validation

Q16. Scaffold hopping in combinatorial chemistry is used to:

  • Replace a core scaffold to find new chemotypes with similar activity
  • Make the scaffold heavier without biological testing
  • Reduce diversity by fixing one scaffold only
  • Eliminate the need for SAR studies

Correct Answer: Replace a core scaffold to find new chemotypes with similar activity

Q17. Which statement about focused combinatorial libraries is true?

  • They explore broad, unrelated chemotypes indiscriminately
  • They are designed around a known active pharmacophore to probe SAR
  • They avoid any relation to an identified target
  • They are not useful for lead optimization

Correct Answer: They are designed around a known active pharmacophore to probe SAR

Q18. One benefit of on-bead screening is:

  • Compounds must be cleaved and purified before any assay
  • Direct affinity screening of bead-displayed compounds without cleavage
  • Bead screening always provides exact potency values
  • It prevents any false positives completely

Correct Answer: Direct affinity screening of bead-displayed compounds without cleavage

Q19. Which factor is critical when designing a combinatorial library to increase hit rates?

  • Including only the largest possible molecules
  • Balancing chemical diversity with drug-like property filters
  • Excluding all heterocycles
  • Ensuring extreme lipophilicity for all members

Correct Answer: Balancing chemical diversity with drug-like property filters

Q20. What is the purpose of positional scanning in mixture-based libraries?

  • To vary all positions simultaneously without tracking
  • To systematically test each position while other positions are mixed
  • To eliminate the need for hit validation
  • To sequence DNA tags only

Correct Answer: To systematically test each position while other positions are mixed

Q21. Which outcome best describes a “hit” from combinatorial screening?

  • A compound or mixture that shows desired activity in an assay
  • A compound that failed all assays
  • A compound that is impossible to synthesize
  • A compound that only affects unrelated enzymes

Correct Answer: A compound or mixture that shows desired activity in an assay

Q22. In DNA-encoded libraries, identification of binders typically relies on:

  • Mass spectrometry of unlabeled mixtures only
  • Sequencing the DNA tags from selected binders
  • Colorimetric changes of DNA in solution
  • Visual inspection of beads

Correct Answer: Sequencing the DNA tags from selected binders

Q23. Which practice reduces false positives during HTS of combinatorial libraries?

  • Using orthogonal confirmatory assays and counterscreens
  • Skipping replicate measurements
  • Relying solely on a single high-signal readout
  • Testing only mixtures with no follow-up

Correct Answer: Using orthogonal confirmatory assays and counterscreens

Q24. One-bead-one-compound libraries are often deconvoluted by:

  • Sequencing the polymer backbone by NMR
  • Eluting and analyzing active beads by mass spectrometry
  • Assuming the entire library is inactive
  • Visually selecting beads by color alone

Correct Answer: Eluting and analyzing active beads by mass spectrometry

Q25. Which descriptor is commonly applied when filtering combinatorial libraries for drug-likeness?

  • Lipinski’s rule of five
  • Only molecular color
  • Boiling point above 300°C
  • Number of chiral centers equals zero

Correct Answer: Lipinski’s rule of five

Q26. Focused vs diversity libraries: which is true?

  • Focused libraries sample broad chemistry unrelated to the target
  • Diversity libraries explore wide chemical space; focused libraries target a known scaffold
  • Both are identical in design purpose
  • Only focused libraries can be screened by HTS

Correct Answer: Diversity libraries explore wide chemical space; focused libraries target a known scaffold

Q27. Which technological advancement most enabled large-scale combinatorial library screening?

  • Automated liquid handling and high-throughput assay platforms
  • Manual pipetting under a microscope
  • Manual synthesis without automation
  • Using only paper chromatography

Correct Answer: Automated liquid handling and high-throughput assay platforms

Q28. What role does structure–activity relationship (SAR) analysis play after combinatorial screening?

  • SAR guides optimization by correlating structural changes with activity changes
  • SAR eliminates the need for chemical synthesis
  • SAR only applies to natural products
  • SAR prevents any further testing of hits

Correct Answer: SAR guides optimization by correlating structural changes with activity changes

Q29. Which is an advantage of using miniaturized assay formats in combinatorial screening?

  • Increased reagent consumption and cost
  • Reduced reagent use, higher throughput, and lower cost per assay
  • Lower sensitivity compared to large-volume assays always
  • Inability to automate assays

Correct Answer: Reduced reagent use, higher throughput, and lower cost per assay

Q30. Hit-to-lead progression after combinatorial screening typically includes:

  • Medicinal chemistry optimization, secondary assays, and ADME profiling
  • Immediate phase III clinical trials without preclinical work
  • Only increasing molecular weight regardless of activity
  • Abandoning any SAR insights

Correct Answer: Medicinal chemistry optimization, secondary assays, and ADME profiling

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