Drug Discovery Stages: lead identification, validation and target diversity MCQs With Answer

Drug Discovery Stages: lead identification, validation and target diversity MCQs With Answer

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Introduction: Drug Discovery Stages: lead identification, validation and target diversity MCQs With Answer is a focused study aid tailored for M.Pharm students tackling MPC 103T Advanced Medicinal Chemistry. This set explains core concepts in lead finding — including high-throughput screening, virtual screening, fragment-based approaches, and natural product leads — and delves into rigorous lead validation strategies like orthogonal biochemical assays, cellular target engagement, SAR and ADMET profiling. It also examines target diversity, druggability, and specific challenges across target families (GPCRs, kinases, PPIs, allosteric sites). Use these MCQs to strengthen conceptual understanding, prepare for exams, and bridge theoretical knowledge with practical strategies used in modern drug discovery.

Q1. Which technique is most directly associated with identifying low-molecular-weight fragments that bind weakly but efficiently to a target for subsequent optimization?

  • High-throughput screening (HTS) of large, drug-like libraries
  • Fragment-based drug discovery (FBDD)
  • Phenotypic screening in whole cells
  • DNA-encoded library selection

Correct Answer: Fragment-based drug discovery (FBDD)

Q2. Which parameter combines potency and molecular size to help prioritize leads with efficient binding relative to size?

  • pKi
  • Ligand efficiency (LE)
  • Partition coefficient (log P)
  • Topological polar surface area (TPSA)

Correct Answer: Ligand efficiency (LE)

Q3. Which assay provides direct evidence of target engagement inside intact cells by measuring thermal stabilization of the protein upon ligand binding?

  • Surface plasmon resonance (SPR)
  • Differential scanning calorimetry (DSC)
  • CETSA (cellular thermal shift assay)
  • Fluorescence polarization (FP)

Correct Answer: CETSA (cellular thermal shift assay)

Q4. Which approach is most appropriate for discovering chemically diverse ligands without prior knowledge of the target (target-agnostic)?

  • Target-based biochemical HTS
  • Fragment growing guided by crystal structures
  • Phenotypic screening
  • Structure-based virtual screening

Correct Answer: Phenotypic screening

Q5. During lead validation, orthogonal assays are used primarily to:

  • increase throughput by running the same assay in duplicate
  • confirm activity by using different assay formats that rule out artifacts
  • optimize synthetic routes to the lead
  • measure the log P of the compound

Correct Answer: confirm activity by using different assay formats that rule out artifacts

Q6. Which of the following is a direct genetic method commonly used for target validation in cellular systems?

  • Surface plasmon resonance
  • CRISPR-Cas9 knockout of the gene encoding the putative target
  • Microsomal stability assay
  • Fragment linking

Correct Answer: CRISPR-Cas9 knockout of the gene encoding the putative target

Q7. DNA-encoded libraries (DELs) are particularly powerful for lead identification because they:

  • require no sequencing to identify hits
  • allow screening of billions of compounds in a single tube with sequencing-based decoding
  • are limited to fragments smaller than 200 Da
  • are only useful for covalent inhibitor discovery

Correct Answer: allow screening of billions of compounds in a single tube with sequencing-based decoding

Q8. Which metric is most useful during lead optimization to account for both potency and lipophilicity improvements?

  • Ligand efficiency (LE)
  • Lipophilic ligand efficiency (LipE / LLE)
  • pKa
  • Molecular weight (MW)

Correct Answer: Lipophilic ligand efficiency (LipE / LLE)

Q9. In target diversity considerations, protein-protein interactions (PPIs) are classically challenging because:

  • PPI interfaces are often large and flat, lacking deep pockets for small molecules
  • PPIs always occur in the nucleus where drugs cannot reach
  • PPIs are allosteric and thus unpredictable
  • PPIs cannot be assayed in vitro

Correct Answer: PPI interfaces are often large and flat, lacking deep pockets for small molecules

Q10. Which concept describes modifying a hit to remove chemical liabilities, improve ADMET and increase the chance of clinical success?

  • Hit triage
  • Lead optimization
  • Target deconvolution
  • High-content screening

Correct Answer: Lead optimization

Q11. A covalent inhibitor strategy is particularly attractive when:

  • the target has a suitably positioned nucleophilic residue and chronic target inactivation is desirable
  • irreversible inhibition is never tolerated
  • the target is extracellular only
  • the ligand must be extremely hydrophilic

Correct Answer: the target has a suitably positioned nucleophilic residue and chronic target inactivation is desirable

Q12. Which in silico method is most directly employed to prioritize compounds by predicting how they fit into a known binding site?

  • Pharmacophore mapping without structural information
  • Structure-based virtual screening (docking)
  • Cell-based phenotypic modeling
  • DNA-encoded library synthesis

Correct Answer: Structure-based virtual screening (docking)

Q13. During lead validation, selectivity profiling is essential because it:

  • determines whether the compound is soluble in water
  • identifies off-target activities that could cause side effects or confound mechanism interpretation
  • shows whether the compound is easy to synthesize
  • replaces the need for ADME testing

Correct Answer: identifies off-target activities that could cause side effects or confound mechanism interpretation

Q14. Scaffold hopping in medicinal chemistry is used to:

  • increase molecular weight without changing activity
  • find structurally distinct cores that retain activity to improve IP position or ADMET
  • convert noncovalent binders into covalent ones
  • sequence DNA-encoded hits

Correct Answer: find structurally distinct cores that retain activity to improve IP position or ADMET

Q15. Which experimental biophysical technique provides kinetic rate constants (kon/koff) and affinities for direct binding measurements in lead discovery?

  • Cell viability assay
  • Surface plasmon resonance (SPR)
  • Microsomal clearance assay
  • Log D determination

Correct Answer: Surface plasmon resonance (SPR)

Q16. In the context of target druggability, which property most directly increases the likelihood that a protein can be modulated by a small molecule?

  • High expression only in a minority of tissues
  • Presence of a well-defined, deep, and ligandable binding pocket
  • High molecular weight (>200 kDa)
  • Exclusive extracellular localization

Correct Answer: Presence of a well-defined, deep, and ligandable binding pocket

Q17. Which outcome from a phenotypic screen typically necessitates target deconvolution as the next step?

  • No observable phenotype
  • A confirmed cellular phenotype with potential therapeutic relevance but unknown molecular target
  • Immediate entry into clinical trials
  • High compound solubility in buffer

Correct Answer: A confirmed cellular phenotype with potential therapeutic relevance but unknown molecular target

Q18. Which ADMET parameter is commonly assessed early during lead selection to predict metabolic stability and potential drug-drug interaction liabilities?

  • hERG channel inhibition only
  • Human liver microsomal stability and CYP inhibition profiling
  • Optical rotation
  • Crystal melting point

Correct Answer: Human liver microsomal stability and CYP inhibition profiling

Q19. Allosteric modulators differ from orthosteric ligands primarily because they:

  • bind at the active site where endogenous ligands bind
  • bind at a distinct site to modulate function and can provide subtype selectivity or ceiling effects
  • always act as irreversible inhibitors
  • are only peptides and cannot be small molecules

Correct Answer: bind at a distinct site to modulate function and can provide subtype selectivity or ceiling effects

Q20. Which approach best reduces false positives that arise from assay interference compounds during hit triage?

  • Rely only on the primary single readout assay
  • Use counter-screens, orthogonal assays and confirm hits in cellular and biophysical assays
  • Prioritize colored compounds as likely actives
  • Ignore aggregation and colloidal behavior

Correct Answer: Use counter-screens, orthogonal assays and confirm hits in cellular and biophysical assays

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