Case studies in analog-based drug design MCQs With Answer

Introduction: Analog-based drug design uses systematic modification of lead compounds to improve potency, selectivity, and ADME properties through case studies and medicinal chemistry strategies. B. Pharm students will explore concepts such as structure-activity relationship (SAR), QSAR modeling, bioisosteres, scaffold hopping, conformational restriction, and linker optimization. Practical case studies reveal how substituent effects, lipophilicity (logP), pKa, metabolic soft spots, and stereochemistry influence efficacy and safety. Integrating computational tools, in vitro assays, and iterative optimization helps translate chemical changes into better drug candidates. This topic strengthens rational decision-making in lead optimization and prepares students for research and development roles. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. What is the primary goal of analog-based drug design in lead optimization?

• To discover completely new molecular scaffolds unrelated to the lead
• To make minor chemical modifications to a lead to improve desired properties
• To increase the molecular weight of the lead as much as possible
• To replace all heteroatoms with carbon

Correct Answer: To make minor chemical modifications to a lead to improve desired properties

Q2. In SAR analysis, what does a systematic series of analogs primarily reveal?

• The solubility of unrelated compounds
• The relationship between structural changes and biological activity
• The cost of synthesis for each analog
• The regulatory status of the lead compound

Correct Answer: The relationship between structural changes and biological activity

Q3. Which strategy involves replacing a problematic functional group with one that has similar biological properties?

• Scaffold hopping
• Bioisosteric replacement
• Prodrug formation
• Fragment linking

Correct Answer: Bioisosteric replacement

Q4. What is a common objective when applying conformational restriction in analog design?

• Increase molecular flexibility to fit multiple targets
• Reduce entropy penalty to improve binding affinity
• Eliminate all chiral centers
• Increase metabolic liability

Correct Answer: Reduce entropy penalty to improve binding affinity

Q5. Which parameter is most directly related to membrane permeability and lipophilicity?

• pKa
• LogP (partition coefficient)
• Molecular refractivity
• Optical rotation

Correct Answer: LogP (partition coefficient)

Q6. In case studies, removal of a nitro group often aims to reduce which liability?

• Poor binding affinity
• Mutagenicity and toxicity
• Increased aqueous solubility
• Reduced lipophilicity

Correct Answer: Mutagenicity and toxicity

Q7. Scaffold hopping is best described as:

• Small substituent changes on the same core scaffold
• Replacing the central scaffold while retaining key pharmacophore features
• Combining two leads into one larger molecule
• Removing all rotatable bonds

Correct Answer: Replacing the central scaffold while retaining key pharmacophore features

Q8. Which in silico method helps predict how analogs interact with a target binding site?

• High-performance liquid chromatography
• Molecular docking
• Thin-layer chromatography
• DSC thermal analysis

Correct Answer: Molecular docking

Q9. What does QSAR modeling correlate with biological activity?

• Only synthetic yield data
• Quantitative molecular descriptors
• Historical patent citations
• Color of the compound

Correct Answer: Quantitative molecular descriptors

Q10. Which modification is commonly used to block metabolic soft spots and improve metabolic stability?

• Adding labile esters
• Introducing fluorine at metabolized positions
• Increasing the number of hydrogen bond donors
• Removing aromatic rings

Correct Answer: Introducing fluorine at metabolized positions

Q11. In analog design, balancing potency and selectivity often requires modifying which feature?

• Color of the crystal form
• Steric and electronic properties of substituents
• Only the solvent used in synthesis
• Number of steps in synthesis

Correct Answer: Steric and electronic properties of substituents

Q12. Which descriptor indicates the polar surface area relevant to oral bioavailability?

• tPSA (topological polar surface area)
• Boiling point
• Melting point
• Refractive index

Correct Answer: tPSA (topological polar surface area)

Q13. What is a key advantage of using fragment-based lead discovery when designing analogs?

• Starting from very large molecules
• Identifying small, efficient fragments to grow into potent analogs
• Eliminating the need for SAR studies
• Guaranteeing oral bioavailability

Correct Answer: Identifying small, efficient fragments to grow into potent analogs

Q14. Which chemical change is often used to improve aqueous solubility of an analog?

• Increase hydrophobic aromatic rings
• Introduce polar ionizable groups or form salts
• Remove all heteroatoms
• Convert all substituents to methyl groups

Correct Answer: Introduce polar ionizable groups or form salts

Q15. Which concept explains how electron-withdrawing substituents affect acidity and binding interactions?

• Le Chatelier’s principle
• Hammett substituent constant (σ)
• Beer-Lambert law
• Arrhenius equation

Correct Answer: Hammett substituent constant (σ)

Q16. When removing a stereocenter in analog design, what potential effect must be considered?

• Only changes in color
• Loss of stereospecific binding and altered activity
• Guaranteed increase in metabolic stability
• Automatic patent protection

Correct Answer: Loss of stereospecific binding and altered activity

Q17. Which assay type is most informative early in analog case studies for potency measurement?

• In vitro biochemical or cell-based potency assays
• Full human clinical trials
• Long-term toxicology in multiple species
• Market analysis studies

Correct Answer: In vitro biochemical or cell-based potency assays

Q18. What is the role of a pharmacophore model in analog-based design?

• To predict synthetic routes
• To define essential spatial features required for activity
• To measure solubility in water
• To estimate production costs

Correct Answer: To define essential spatial features required for activity

Q19. Prodrug strategies in analog design are typically used to:

• Convert active drugs into less active forms permanently
• Improve properties like solubility, permeability, or targeting prior to activation
• Increase the number of stereocenters
• Eliminate the need for metabolic activation

Correct Answer: Improve properties like solubility, permeability, or targeting prior to activation

Q20. Which modification can improve selectivity by sterically blocking off-target binding?

• Adding bulky substituents near the interaction site
• Reducing molecular weight to under 100 Da
• Removing all aromatic rings
• Introducing flexible long alkyl chains

Correct Answer: Adding bulky substituents near the interaction site

Q21. In a case study, replacing a metabolically labile methyl with a fluorine primarily affects:

• Optical rotation
• Metabolic stability and C–H bond strength
• Number of rotatable bonds
• Color of the compound

Correct Answer: Metabolic stability and C–H bond strength

Q22. Which property is commonly optimized to reduce CYP-mediated drug–drug interactions in analogs?

• Increase pKa above 14
• Reduce CYP inhibition potential by modifying structural motifs
• Ensure the molecule is completely hydrophobic
• Maximize number of aromatic nitro groups

Correct Answer: Reduce CYP inhibition potential by modifying structural motifs

Q23. What does ‘lead-likeness’ typically imply when selecting analogs for optimization?

• Very large molecular weight and high lipophilicity
• Balanced physicochemical properties amenable to optimization
• Complete lack of polar groups
• Guaranteed clinical success

Correct Answer: Balanced physicochemical properties amenable to optimization

Q24. In SAR tables from case studies, a steep activity cliff indicates:

• Minor structural change gives large activity change
• No relationship between structure and activity
• All analogs have identical activity
• A failure in assay quality

Correct Answer: Minor structural change gives large activity change

Q25. Which approach reduces off-target ionization problems and improves membrane crossing?

• Adding multiple strong bases
• Optimizing pKa to favor the unionized form at physiological pH
• Adding multiple sulfonate groups
• Increasing tPSA above 200 Ų

Correct Answer: Optimizing pKa to favor the unionized form at physiological pH

Q26. Which experimental technique helps map metabolic soft spots in a lead compound?

• In vitro microsomal stability and metabolite identification
• UV-Vis spectroscopy of the solid
• Elemental analysis
• Melting point determination

Correct Answer: In vitro microsomal stability and metabolite identification

Q27. When analogs show increased potency but poor pharmacokinetics, the next step is usually to:

• Abandon the program entirely
• Modify the scaffold to balance PK while retaining potency
• Increase the molecular weight further
• Skip ADME testing

Correct Answer: Modify the scaffold to balance PK while retaining potency

Q28. Which consideration is essential for patent strategy in analog-based design?

• Ensure analogs are identical to prior art
• Create non-obvious chemical modifications that provide improved properties
• Publish all structures without filing patents
• Only make changes that are trivial and well-known

Correct Answer: Create non-obvious chemical modifications that provide improved properties

Q29. In many case studies, why is stereochemical purity of an analog important?

• Stereochemistry never affects biological activity
• Enantiomers can have different potency, metabolism, and safety profiles
• Pure stereochemistry always reduces synthesis cost
• Regulatory agencies forbid chiral centers

Correct Answer: Enantiomers can have different potency, metabolism, and safety profiles

Q30. Which integrated workflow is most effective for analog-based design in modern case studies?

• Only synthesis without biological testing
• Iterative cycles of design, synthesis, in vitro/in vivo testing, and computational analysis
• Immediate human trials after the first analog
• Choosing analogs randomly without data

Correct Answer: Iterative cycles of design, synthesis, in vitro/in vivo testing, and computational analysis

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