Structure–activity relationship (SAR) MCQs With Answer effectively give B. Pharm students focused practice on how chemical structure controls pharmacological activity. These multiple-choice questions explore SAR concepts such as pharmacophore mapping, electronic and steric influences, lipophilicity (logP), pKa, hydrogen bonding, bioisosteres and stereochemistry. They also cover quantitative tools such as QSAR, 3D QSAR, CoMFA, Hansch and Free-Wilson approaches, plus ADME, metabolic liability, lead optimization, scaffold modification and descriptor interpretation. The set emphasizes application: reading SAR tables, predicting potency changes after substitutions and proposing modifications to improve selectivity and drug-like properties. Now let’s test your knowledge with 30 MCQs on this topic.
Q1. Which molecular property is most directly quantified by logP in SAR analysis?
- Ionization constant
- Hydrophobicity (lipophilicity)
- Hydrogen bond donor count
- Steric bulk
Correct Answer: Hydrophobicity (lipophilicity)
Q2. The Hammett sigma constant describes which effect of a substituent on activity?
- Steric hindrance
- Electronic (inductive/resonance) effect
- Lipophilicity
- Conformational flexibility
Correct Answer: Electronic (inductive/resonance) effect
Q3. In Free‑Wilson analysis, what is required to quantify substituent contributions?
- 3D structure of the target protein
- Series of analogues with systematic substitution
- Single high affinity ligand
- Microsomal stability data
Correct Answer: Series of analogues with systematic substitution
Q4. Which descriptor is most important when predicting passive membrane permeability?
- Topological polar surface area (TPSA)
- Number of rotatable bonds only
- Optical rotation
- UV absorption maxima
Correct Answer: Topological polar surface area (TPSA)
Q5. What is a primary advantage of using bioisosteres in SAR-driven lead optimization?
- Increase molecular weight only
- Replace a group to retain activity while modifying ADME or toxicity
- Make molecules more flexible
- Ensure compounds are achiral
Correct Answer: Replace a group to retain activity while modifying ADME or toxicity
Q6. Activity cliffs in SAR describe which phenomenon?
- Gradual linear increase in potency with molecular size
- Small structural change causing large potency change
- Loss of solubility with increasing lipophilicity
- Convergence of multiple analogues to same potency
Correct Answer: Small structural change causing large potency change
Q7. Which 3D‑QSAR method visualizes steric and electrostatic contour maps?
- Hansch analysis
- CoMFA (Comparative Molecular Field Analysis)
- Free‑Wilson analysis
- Matched molecular pair analysis
Correct Answer: CoMFA (Comparative Molecular Field Analysis)
Q8. In Hansch QSAR, what types of terms are typically included in the regression equation?
- Only topological indices
- Lipophilicity (pi), electronic constants, and steric parameters
- Only experimental ADME values
- Only protein crystal contact energies
Correct Answer: Lipophilicity (pi), electronic constants, and steric parameters
Q9. Which change is most likely to increase basic drug absorption in the stomach?
- Decrease pKa to below 2
- Increase pKa so more of the drug is protonated at low pH
- Convert to a permanently neutral compound
- Increase molecular polarity dramatically
Correct Answer: Increase pKa so more of the drug is protonated at low pH
Q10. Matched molecular pair analysis is primarily used to:
- Compare two unrelated scaffolds for patentability
- Assess the effect of a single structural change on properties
- Calculate absolute binding free energy
- Determine crystal packing interactions
Correct Answer: Assess the effect of a single structural change on properties
Q11. Which stereochemical factor commonly influences receptor selectivity in SAR?
- Presence of aromatic rings only
- Absolute configuration (R/S) of chiral centers
- Molecular weight regardless of shape
- Number of tertiary amines only
Correct Answer: Absolute configuration (R/S) of chiral centers
Q12. Which modification is a typical strategy to reduce metabolic clearance in lead optimization?
- Add multiple primary alcohols
- Introduce metabolically stable bioisosteres or steric shielding near metabolic hotspots
- Increase polar surface area to >200 Ų
- Replace aromatic rings with unsubstituted cyclohexane always
Correct Answer: Introduce metabolically stable bioisosteres or steric shielding near metabolic hotspots
Q13. What does the term ‘pharmacophore’ refer to in SAR?
- The full 3D structure of the protein target
- Minimal spatial arrangement of features necessary for activity
- Only the most lipophilic part of a molecule
- Crystal packing contacts in a ligand complex
Correct Answer: Minimal spatial arrangement of features necessary for activity
Q14. Which descriptor captures electronic withdrawing or donating tendency of substituents?
- Hammett sigma constant
- Octanol–water partition coefficient (logP)
- Rotatable bond count
- Topological polar surface area (TPSA)
Correct Answer: Hammett sigma constant
Q15. Overfitting in QSAR modeling occurs when:
- The model is too simple to explain training data
- The model fits noise in the training set and performs poorly on external data
- The model uses validated external test sets
- Descriptors are biologically interpretable
Correct Answer: The model fits noise in the training set and performs poorly on external data
Q16. A prototypical bioisostere replacement to reduce basicity of an aniline is:
- Replace aniline with nitro group
- Replace NH2 with a heterocycle like pyridine
- Replace benzene with aliphatic chain
- Remove aromaticity entirely
Correct Answer: Replace NH2 with a heterocycle like pyridine
Q17. Which SAR observation suggests a hydrogen bond donor is critical for binding?
- Replacing OH with OMe abolishes activity
- Increasing lipophilicity increases activity linearly
- Alkyl chain length has no effect
- Changing stereochemistry has no effect
Correct Answer: Replacing OH with OMe abolishes activity
Q18. In QSAR, multicollinearity among descriptors leads to:
- More robust, interpretable models
- Unstable regression coefficients and poor interpretability
- Decreased risk of overfitting always
- Higher predictive power on external sets
Correct Answer: Unstable regression coefficients and poor interpretability
Q19. Which technique helps identify 3D arrangement of pharmacophoric features from a set of active ligands?
- Pharmacophore modeling
- Microsomal stability assay
- HPLC purity analysis
- pKa titration
Correct Answer: Pharmacophore modeling
Q20. Which change would most likely reduce blood–brain barrier penetration?
- Decrease TPSA and increase lipophilicity
- Increase polar surface area and add an ionizable group
- Reduce molecular weight below 200 Da
- Convert to a neutral nonpolar scaffold
Correct Answer: Increase polar surface area and add an ionizable group
Q21. What is the main purpose of an applicability domain in QSAR?
- Define chemical space where model predictions are reliable
- Ensure models cover all known drugs
- Maximize the number of descriptors used
- Guarantee 100% prediction accuracy
Correct Answer: Define chemical space where model predictions are reliable
Q22. Which experimental change indicates a metabolic soft spot near a substituent?
- Unchanged metabolite profile across analogues
- Formation of a common oxidative metabolite at that position
- Decreased potency only in vitro binding assays
- Improved solubility with no metabolic change
Correct Answer: Formation of a common oxidative metabolite at that position
Q23. Which descriptor combination often improves QSAR for potency prediction?
- Only molecular weight and melting point
- Combined electronic, steric and lipophilicity descriptors
- Only the number of hydrogen bond donors
- Only the number of aromatic rings
Correct Answer: Combined electronic, steric and lipophilicity descriptors
Q24. Scaffold hopping in SAR aims to:
- Increase the number of rotatable bonds
- Change core scaffold to retain activity while altering properties or IP
- Make molecules more metabolically vulnerable
- Keep the scaffold identical while modifying peripheral groups only
Correct Answer: Change core scaffold to retain activity while altering properties or IP
Q25. Which SAR strategy helps improve selectivity over an off‑target enzyme?
- Increase general lipophilicity without considering binding site differences
- Exploit structural differences in active sites to add selective interactions
- Remove polar interactions universally
- Reduce molecular rigidity to increase conformational sampling
Correct Answer: Exploit structural differences in active sites to add selective interactions
Q26. Which validation metric assesses internal predictive ability during QSAR model building?
- External test set R²
- Leave‑one‑out cross‑validated Q²
- Number of descriptors used
- Melting point correlation
Correct Answer: Leave‑one‑out cross‑validated Q²
Q27. Changing a tertiary amine to a tertiary amide usually affects SAR by:
- Increasing basicity and membrane permeability
- Reducing basicity and often decreasing permeability
- Removing all polar surface area
- Always increasing potency
Correct Answer: Reducing basicity and often decreasing permeability
Q28. Which observation suggests that steric bulk near a binding region is tolerated?
- Large substituents at that position retain or improve potency
- Small substituents cause complete loss of activity
- Changing substituents never affects potency
- Only polar changes alter activity
Correct Answer: Large substituents at that position retain or improve potency
Q29. Why is descriptor selection important before QSAR model fitting?
- To include as many correlated descriptors as possible
- To reduce noise, avoid multicollinearity and improve interpretability
- Because descriptors do not affect model quality
- To ensure all descriptors are categorical
Correct Answer: To reduce noise, avoid multicollinearity and improve interpretability
Q30. Which approach helps prioritize analogues with better oral bioavailability during SAR?
- Maximize lipophilicity without limit
- Balance potency with physicochemical properties (logP, TPSA, MW) and metabolic stability
- Only focus on increasing molecular weight
- Design solely for maximum receptor affinity regardless of ADME
Correct Answer: Balance potency with physicochemical properties (logP, TPSA, MW) and metabolic stability
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