QSAR: history, concepts and physicochemical parameters MCQs With Answer

Introduction: QSAR (Quantitative Structure–Activity Relationship) is a cornerstone of modern medicinal chemistry that links molecular structure with biological activity using mathematical models. This blog provides M. Pharm students with focused multiple-choice practice on the history, core concepts, and essential physicochemical parameters used in QSAR modeling. Questions emphasize landmark developments (Hammett, Hansch, Free–Wilson), descriptor types (constitutional, topological, electronic, steric), lipophilicity and ionization metrics (logP, logD, pKa), model-building techniques (MLR, PLS, genetic selection), validation practices (cross-validation, external predictivity), and practical limitations such as applicability domain and overfitting. These MCQs deepen conceptual understanding and prepare students for exams and research applications.

Q1. Who introduced the Hammett equation that established linear free-energy relationships in physical organic chemistry?

• Louis P. Hammett
• Corwin Hansch
• Charles A. Free and Maurice N. Wilson
• Arthur C. Cope

Correct Answer: Louis P. Hammett

Q2. Which scientist is credited with pioneering the classical QSAR approach that incorporated lipophilicity (logP) and electronic substituent constants into activity correlations?

• Corwin Hansch
• Louis P. Hammett
• Ernest E. van Tamelen
• John P. A. Ioannidis

Correct Answer: Corwin Hansch

Q3. What is the basic principle of the Free–Wilson method in QSAR?

• Treat overall activity as additive contributions of substituents at defined positions
• Model activity solely using molecular lipophilicity (logP)
• Predict 3D binding modes using docking
• Estimate solubility from polar surface area

Correct Answer: Treat overall activity as additive contributions of substituents at defined positions

Q4. Which descriptor specifically represents the pH-dependent distribution of an ionizable compound between octanol and water?

• logP (partition coefficient)
• logD (distribution coefficient)
• pKa (acid dissociation constant)
• TPSA (topological polar surface area)

Correct Answer: logD (distribution coefficient)

Q5. According to Lipinski’s Rule of Five, what is the maximum recommended number of hydrogen bond donors for good oral bioavailability?

• 2
• 5
• 8
• 10

Correct Answer: 5

Q6. What does the pKa of a molecule represent?

• The partition coefficient between octanol and water
• The negative logarithm of the acid dissociation constant (Ka)
• The molecular weight divided by volume
• The topological polar surface area

Correct Answer: The negative logarithm of the acid dissociation constant (Ka)

Q7. Molar refractivity is commonly used in QSAR as an indicator of which molecular property?

• Hydrogen bond donor count
• Polarizability and molecular volume (steric/dispersion interactions)
• Acid strength (pKa)
• Topological complexity

Correct Answer: Polarizability and molecular volume (steric/dispersion interactions)

Q8. Topological polar surface area (TPSA) is mainly used to predict which ADME property?

• Metabolic clearance by CYP enzymes
• Oral absorption and passive membrane permeability
• P-glycoprotein binding affinity
• Protein plasma binding percentage

Correct Answer: Oral absorption and passive membrane permeability

Q9. Which of the following is an electronic substituent constant frequently used in QSAR studies?

• Hammett sigma (σ) constant
• Topological polar surface area (TPSA)
• Molecular weight (MW)
• Rotatable bond count

Correct Answer: Hammett sigma (σ) constant

Q10. Which observation during model development is a classic indicator of overfitting in QSAR?

• Low training set r2 and low cross-validated q2
• High training set r2 but much lower cross-validated q2
• High external prediction R2 and low RMSEP
• Model uses only one descriptor

Correct Answer: High training set r2 but much lower cross-validated q2

Q11. Which multivariate method is particularly effective for handling descriptor multicollinearity in QSAR modeling?

• Multiple linear regression (MLR) without preprocessing
• Partial least squares (PLS) regression
• Simple linear correlation
• K-means clustering

Correct Answer: Partial least squares (PLS) regression

Q12. Which descriptor selection technique uses evolution-inspired operators (selection, crossover, mutation) to identify informative variables?

• Forward stepwise selection
• Principal component analysis (PCA)
• Genetic algorithm (GA)-based selection
• Hierarchical clustering

Correct Answer: Genetic algorithm (GA)-based selection

Q13. How is the applicability domain of a QSAR model commonly defined?

• By the software used to build the model
• By the chemical space and descriptor ranges represented in the training set (using leverage or distance metrics)
• By the largest molecular weight in the library only
• By the number of descriptors included, irrespective of values

Correct Answer: By the chemical space and descriptor ranges represented in the training set (using leverage or distance metrics)

Q14. Which combination of validation metrics best indicates strong external predictivity of a QSAR model?

• Low external R2 and high RMSEP
• High external R2 (R2pred) and low RMSEP
• High training R2 only
• High descriptor count and high Q2

Correct Answer: High external R2 (R2pred) and low RMSEP

Q15. Which of the following is an example of a constitutional descriptor?

• Molecular weight (MW)
• HOMO–LUMO energy gap
• Electrostatic potential map
• Molecular field interaction energies

Correct Answer: Molecular weight (MW)

Q16. Which computational approach is typically used to calculate quantum-mechanical electronic descriptors such as HOMO and LUMO energies?

• Empirical logP calculators only
• Density functional theory (DFT) or ab initio quantum calculations
• Topological index counting
• Rule-of-five filters

Correct Answer: Density functional theory (DFT) or ab initio quantum calculations

Q17. Which physicochemical parameter most directly correlates with hydrophobicity and often influences membrane permeability and nonspecific binding?

• logP (octanol–water partition coefficient)
• pKa
• Topological polar surface area (TPSA)
• Number of rotatable bonds

Correct Answer: logP (octanol–water partition coefficient)

Q18. Which steric parameter developed by Taft is used in QSAR to quantify steric effects of substituents?

• Taft steric parameter (Es)
• Hammett sigma constant (σ)
• Molar refractivity (MR)
• Topological polar surface area (TPSA)

Correct Answer: Taft steric parameter (Es)

Q19. In the classical Hansch equation, what is the role of the term involving the coefficient multiplied by logP?

• To account for electronic effects of substituents
• To represent the influence of lipophilicity on biological activity
• To model stereochemical orientation in 3D space
• To compute solubility directly

Correct Answer: To represent the influence of lipophilicity on biological activity

Q20. What is a major limitation of 2D-QSAR approaches compared to 3D-QSAR methods?

• 2D-QSAR always requires quantum mechanical descriptors
• 2D-QSAR cannot account for 3D conformation, stereochemistry, and specific receptor–ligand spatial interactions
• 2D-QSAR provides exact binding energies
• 2D-QSAR is computationally more expensive than molecular dynamics

Correct Answer: 2D-QSAR cannot account for 3D conformation, stereochemistry, and specific receptor–ligand spatial interactions

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