Principles of drug screening models MCQs With Answer

Introduction: This quiz collection on Principles of Drug Screening Models is designed for M.Pharm students preparing for advanced exams and practical applications in Biological Evaluation of Drug Therapy. It focuses on conceptual understanding and critical evaluation of screening strategies, assay design, in vitro and in vivo model selection, validation metrics and translational relevance. Questions emphasize differences between target‑based and phenotypic approaches, HTS principles, assay robustness (e.g., Z’ factor), ADMET considerations, ethical use of animal models, and interpretation of potency parameters like IC50/EC50. Use these MCQs to strengthen decision‑making skills for selecting and optimizing screening models during drug discovery and preclinical evaluation.

Q1. Which screening approach is primarily focused on modulating a predefined biological target with known molecular identity?

• Phenotypic screening using whole‑cell readouts
• Target‑based screening using biochemical or cell‑based assays
• High‑content imaging of complex phenotypes
• In vivo behavioural screening without defined molecular target

Correct Answer: Target‑based screening using biochemical or cell‑based assays

Q2. Which metric assesses the dynamic range and variability of a high‑throughput assay and is commonly used to judge assay quality?

• EC50
• Signal‑to‑noise ratio (S/N)
• Z’ factor
• Area under the curve (AUC)

Correct Answer: Z’ factor

Q3. Which parameter best describes the concentration of a drug that produces 50% of its maximal effect in a functional assay?

• IC50
• ED50
• EC50
• LD50

Correct Answer: EC50

Q4. In drug screening, a primary screen is mainly intended to:

• Determine clinical dosing and toxicity in humans
• Identify preliminary active compounds (hits) from a large library
• Perform detailed mechanism of action studies
• Optimize pharmacokinetic properties

Correct Answer: Identify preliminary active compounds (hits) from a large library

Q5. Phenotypic screening is advantageous over target‑based screening when:

• The molecular target is well validated and structurally characterized
• Complex cellular responses or unknown targets drive disease biology
• High‑throughput biochemical assays are readily available
• Structure‑based drug design is the preferred strategy

Correct Answer: Complex cellular responses or unknown targets drive disease biology

Q6. Which of the following is a major limitation of biochemical (target‑based) assays?

• They cannot be miniaturized for HTS
• They often fail to capture cell permeability and metabolism issues
• They always require live animals
• They produce overly complex multiparametric outputs

Correct Answer: They often fail to capture cell permeability and metabolism issues

Q7. For an HTS campaign, a logical next step after hit identification is:

• Immediate progression to clinical trials
• Secondary screening and validation of hits to confirm activity and specificity
• Discard hits without any follow‑up
• Direct formulation into dosage forms

Correct Answer: Secondary screening and validation of hits to confirm activity and specificity

Q8. Which in vitro model provides higher physiological relevance for ADME and toxicity screening compared to immortalized cell lines?

• Primary human hepatocytes
• Prokaryotic expression systems
• Simple enzyme assays
• Yeast two‑hybrid systems

Correct Answer: Primary human hepatocytes

Q9. What does a low Z’ factor (<0.5) indicate about an assay?

• Excellent assay separation between positive and negative controls
• Poor assay robustness and high variability
• High throughput with reliable results
• Assay is perfectly optimized for screening

Correct Answer: Poor assay robustness and high variability

Q10. Which statement best reflects the 3Rs principle guiding animal use in preclinical screening?

• Rescue, Recycle, Reattempt
• Reduce, Replace, Refine
• Randomize, Reproduce, Report
• Replicate, Reassess, Revalidate

Correct Answer: Reduce, Replace, Refine

Q11. In a cell viability assay using metabolic activity as a readout, which artifact could falsely appear as increased potency?

• Compound fluorescence quenching the readout dye
• Compound increases metabolic enzyme activity without affecting viability
• Proper negative and positive controls included
• Use of freshly prepared reagent

Correct Answer: Compound increases metabolic enzyme activity without affecting viability

Q12. Which type of screening library is most suitable when exploring chemical diversity to find novel scaffolds?

• Focused library of known inhibitors of a single enzyme family
• Fragment library with low molecular weight compounds
• Diversity‑oriented library covering broad chemical space
• Single high‑affinity ligand library

Correct Answer: Diversity‑oriented library covering broad chemical space

Q13. Which readout is most appropriate for a target engagement assay confirming direct binding to a protein in cells?

• In vitro enzyme kinetics with purified protein only
• CETSA (Cellular Thermal Shift Assay) or target‑based BRET/FRET assays
• Animal survival studies without pharmacodynamic measures
• Global transcriptomics without biochemical confirmation

Correct Answer: CETSA (Cellular Thermal Shift Assay) or target‑based BRET/FRET assays

Q14. When designing a screening cascade, the primary purpose of counter‑screens is to:

• Increase compound library size
• Eliminate false positives arising from assay interference or promiscuous mechanisms
• Replace secondary assays
• Directly measure clinical efficacy

Correct Answer: Eliminate false positives arising from assay interference or promiscuous mechanisms

Q15. Which animal model characteristic is most critical when selecting an in vivo disease model for efficacy screening?

• Ease of handling only
• High cost regardless of relevance
• Physiological and pathophysiological relevance to the human disease
• Availability of many unrelated adjuvants

Correct Answer: Physiological and pathophysiological relevance to the human disease

Q16. In a competitive binding assay, a shift in IC50 for a reference ligand in presence of a test compound indicates:

• Non‑specific aggregation of all proteins
• Potential competition at the same binding site or allosteric modulation
• That the test compound is inactive
• Immediate cytotoxicity unrelated to binding

Correct Answer: Potential competition at the same binding site or allosteric modulation

Q17. Which is a key advantage of miniaturization (e.g., 384‑ or 1536‑well plates) in HTS?

• Increased reagent consumption
• Decreased throughput due to complex handling
• Lower reagent costs and increased throughput with less sample volume
• Reduced need for controls

Correct Answer: Lower reagent costs and increased throughput with less sample volume

Q18. A high false negative rate in a screen most likely results from:

• Too sensitive detection method and low variability
• Inadequate assay sensitivity, suboptimal compound concentrations or poor assay conditions
• Excessive positive controls
• Perfectly optimized assay conditions with high Z’ factor

Correct Answer: Inadequate assay sensitivity, suboptimal compound concentrations or poor assay conditions

Q19. Which statement about translational validity of preclinical screening models is correct?

• All animal models reliably predict human efficacy and safety
• Model selection should consider genetic, molecular and pathophysiological similarity to human disease to improve translation
• Translation depends solely on compound potency in vitro
• In vitro assays eliminate the need for in vivo confirmation

Correct Answer: Model selection should consider genetic, molecular and pathophysiological similarity to human disease to improve translation

Q20. Which assay characteristic is least desirable when prioritizing hits for progression into medicinal chemistry?

• High potency with acceptable selectivity and predictable ADMET
• Activity due to colloidal aggregation or assay interference
• Reproducible activity across orthogonal assays
• Favourable physicochemical properties for optimization

Correct Answer: Activity due to colloidal aggregation or assay interference

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