Hansch analysis and Free-Wilson analysis MCQs With Answer

Introduction: Hansch analysis and Free-Wilson analysis MCQs With Answer is designed for M.Pharm students studying Principles of Drug Discovery. This blog offers a focused set of multiple-choice questions that deepen understanding of quantitative structure–activity relationship (QSAR) methods—specifically the Hansch approach, which links biological activity to continuous physicochemical descriptors (lipophilicity, electronic, steric), and the Free-Wilson method, which uses indicator variables for substituent contributions. The questions explore model building, interpretation of coefficients, mathematical forms, validation metrics, limitations and practical applications in lead optimization. Each MCQ includes options and the correct answer to support exam preparation and applied learning in medicinal chemistry and computational pharmaceutics.

Q1. What is the primary objective of Hansch analysis in drug discovery?

• To correlate biological activity with physicochemical properties of substituents
• To classify compounds into biosynthetic pathways
• To predict clinical trial outcomes
• To design synthetic routes for target molecules

Correct Answer: To correlate biological activity with physicochemical properties of substituents

Q2. In Hansch QSAR, the substituent constant π (pi) primarily represents which property?

• Hydrophobic (lipophilic) substituent constant
• Hammett electronic constant
• Steric (Taft) constant
• Molar refractivity

Correct Answer: Hydrophobic (lipophilic) substituent constant

Q3. What is the basic principle behind Free-Wilson analysis?

• Correlating activity with presence/absence of specific substituents using indicator variables
• Using only 3D molecular fields to predict activity
• Deriving QSAR from docking scores exclusively
• Modeling ADME properties from lipophilicity alone

Correct Answer: Correlating activity with presence/absence of specific substituents using indicator variables

Q4. Which of the following represents a simple linear form of the Hansch equation?

• Activity = a + b·π + c·σ + d·MR (linear form)
• Activity = docking score + ADME coefficient
• Activity = logP × molecular weight
• Activity = pKa / solubility

Correct Answer: Activity = a + b·π + c·σ + d·MR (linear form)

Q5. If a Hansch model yields a negative coefficient for π (pi), what is the interpretation?

• Increased lipophilicity of substituents decreases biological activity
• Increased lipophilicity of substituents increases biological activity
• Lipophilicity has no effect on activity
• Lipophilicity only affects toxicity, not activity

Correct Answer: Increased lipophilicity of substituents decreases biological activity

Q6. Free-Wilson analysis typically encodes substituent effects using which type of variables?

• Binary (indicator) variables
• Continuous physicochemical descriptors
• 3D grid-based interaction fields
• Docking energy scores

Correct Answer: Binary (indicator) variables

Q7. What is the major statistical problem when descriptors used in a Hansch model are highly correlated?

• Multicollinearity, reducing coefficient interpretability
• Heteroscedasticity of residuals
• Increased external predictive power
• Guarantee of overfitting-free model

Correct Answer: Multicollinearity, reducing coefficient interpretability

Q8. Which validation statistic is commonly used to measure internal predictive ability of a QSAR model (leave-one-out cross-validation)?

• q² (cross-validated R²)
• Standard R² (training fit)
• Mean docking score
• BIC (Bayesian Information Criterion)

Correct Answer: q² (cross-validated R²)

Q9. In QSAR modeling, what does the domain of applicability describe?

• The chemical space over which model predictions are considered reliable
• The range of temperatures for experimental assays
• The set of biological targets unrelated to the model
• The physical storage conditions for compounds

Correct Answer: The chemical space over which model predictions are considered reliable

Q10. When should a quadratic term (π²) be included in a Hansch equation?

• When activity shows a parabolic relationship with lipophilicity
• When activity is strictly linear with lipophilicity
• Only when dataset size is less than five
• When descriptors are uncorrelated

Correct Answer: When activity shows a parabolic relationship with lipophilicity

Q11. Which assumption of the original Free-Wilson approach can be limiting in practice?

• Additivity: substituent contributions are independent and additive
• Requires quantum mechanical calculations for each substituent
• Assumes all substituents are identical
• Predicts ADME properties directly

Correct Answer: Additivity: substituent contributions are independent and additive

Q12. In Hansch analysis, the symbol σ (sigma) denotes which substituent constant?

• Hammett electronic (inductive/resonance) constant
• Hydrophobic constant
• Steric Taft constant
• Molar refractivity

Correct Answer: Hammett electronic (inductive/resonance) constant

Q13. What physical property is represented by MR in Hansch equations?

• Molar refractivity (measure of polarizability/steric bulk)
• Molecular radius
• Mass-to-residue ratio
• Membrane retention index

Correct Answer: Molar refractivity (measure of polarizability/steric bulk)

Q14. Which practice helps prevent overfitting when building Hansch or Free-Wilson models?

• Use cross-validation and limit the number of descriptors relative to observations
• Include as many descriptors as possible regardless of dataset size
• Never perform external validation
• Always use squared and interaction terms by default

Correct Answer: Use cross-validation and limit the number of descriptors relative to observations

Q15. Which software/tool is commonly used for statistical QSAR modeling including Hansch and Free-Wilson approaches?

• QSARINS
• AutoDock Vina
• GROMACS
• PyMOL

Correct Answer: QSARINS

Q16. If a Hansch model returns a positive coefficient for σ (Hammett constant where positive values = electron-withdrawing), what does this imply?

• Electron-withdrawing substituents tend to increase biological activity
• Electron-withdrawing substituents decrease biological activity
• Electronic effects have no influence
• Only steric effects matter

Correct Answer: Electron-withdrawing substituents tend to increase biological activity

Q17. In Free-Wilson encoding for a substituent at a particular position, what numeric values are typically used?

• 1 if substituent is present, 0 if absent (binary encoding)
• -1 if present, 1 if absent
• Continuous value proportional to docking score
• Fractional occupancy between 0 and 1

Correct Answer: 1 if substituent is present, 0 if absent (binary encoding)

Q18. Which statement best contrasts Hansch and Free-Wilson approaches?

• Hansch uses continuous physicochemical descriptors; Free-Wilson uses indicator variables for substituents
• Free-Wilson uses continuous descriptors; Hansch uses indicator variables
• Both exclusively use 3D conformational fields
• Neither method can be applied to lead optimization

Correct Answer: Hansch uses continuous physicochemical descriptors; Free-Wilson uses indicator variables for substituents

Q19. Which metric is specifically used to assess external predictive performance of a QSAR model?

• External predictive R² (R²_pred)
• Training set R²
• q² (leave-one-out cross-validated R²)
• Number of descriptors

Correct Answer: External predictive R² (R²_pred)

Q20. What is an effective strategy to handle collinear descriptors in Hansch QSAR?

• Apply dimensionality reduction (PCA) or use PLS regression to reduce collinearity
• Keep all collinear descriptors to increase model complexity
• Randomly shuffle descriptor values to break correlation
• Always remove descriptors that have any correlation coefficient > 0.1

Correct Answer: Apply dimensionality reduction (PCA) or use PLS regression to reduce collinearity

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