Computational drug design methods MCQs With Answer

Introduction: Computational drug design methods integrate structural biology, chemistry, and informatics to accelerate lead identification and optimization in pharmaceutical research. For M.Pharm students, mastering approaches such as structure-based and ligand-based design, molecular docking, virtual screening, QSAR, pharmacophore modeling, molecular dynamics, and free-energy calculations is essential for rational drug discovery. This blog provides targeted multiple-choice questions with answers to deepen conceptual understanding, emphasize practical considerations (force fields, scoring functions, validation metrics), and link computational predictions to ADMET and experimental follow-up. The set focuses on typical challenges encountered in academia and industry, preparing students for research projects and competitive examinations in bioinformatics and computational biotechnology.

Q1. What is the primary difference between structure-based drug design (SBDD) and ligand-based drug design (LBDD)?

• SBDD uses the 3D structure of the target protein while LBDD relies on known active ligands
• SBDD is used only for small molecules and LBDD only for biologics
• SBDD does not require any computational tools while LBDD does
• SBDD always yields better ADMET profiles than LBDD

Correct Answer: SBDD uses the 3D structure of the target protein while LBDD relies on known active ligands

Q2. Which of the following best describes molecular docking?

• A technique to predict the most probable binding pose and orientation of a ligand in a protein active site
• A method to compute absolute solubility of compounds in water
• A laboratory assay to measure binding kinetics
• A statistical tool to analyze clinical trial outcomes

Correct Answer: A technique to predict the most probable binding pose and orientation of a ligand in a protein active site

Q3. In docking scoring functions, which energy term commonly estimates electrostatic interactions?

• Van der Waals term
• Hydrophobic contact score
• Coulombic (electrostatic) term
• Entropy penalty term

Correct Answer: Coulombic (electrostatic) term

Q4. Which method provides a more rigorous estimate of relative binding free energies between two ligands?

• Docking score from a single rigid receptor docking
• MM-PBSA or MM-GBSA calculations on molecular dynamics trajectories
• Simple molecular weight comparison
• 2D similarity-based fingerprint Tanimoto score

Correct Answer: MM-PBSA or MM-GBSA calculations on molecular dynamics trajectories

Q5. What role do force fields (e.g., AMBER, CHARMM) play in computational drug design?

• They define mathematical functions and parameters to model bonded and non-bonded interactions in molecular simulations
• They automatically generate pharmacokinetic predictions for new compounds
• They are used only for image rendering of molecular structures
• They replace the need for any experimental validation

Correct Answer: They define mathematical functions and parameters to model bonded and non-bonded interactions in molecular simulations

Q6. Which descriptor type is most commonly used in QSAR models for predicting biological activity?

• 2D/3D molecular descriptors such as logP, polar surface area, and topological indices
• Clinical trial endpoints like survival rate
• Protein crystallization conditions
• Vendor catalog numbers

Correct Answer: 2D/3D molecular descriptors such as logP, polar surface area, and topological indices

Q7. What is the principal advantage of ensemble docking over single-structure docking?

• Ensemble docking accounts for receptor flexibility by using multiple protein conformations
• Ensemble docking eliminates the need for scoring functions
• Ensemble docking only uses ligand conformers and ignores the protein
• Ensemble docking is faster and requires no computing resources

Correct Answer: Ensemble docking accounts for receptor flexibility by using multiple protein conformations

Q8. Which validation metric is commonly used to assess virtual screening performance with actives and decoys?

• Enrichment factor (EF) and ROC-AUC
• Root mean square deviation (RMSD) of ligand bond lengths
• pH of the assay buffer
• LC-MS retention time

Correct Answer: Enrichment factor (EF) and ROC-AUC

Q9. In docking studies, what does RMSD between docked and experimental ligand pose indicate?

• The closeness of predicted pose to the experimentally observed binding mode
• The solubility of the ligand in aqueous solution
• The number of hydrogen bonds formed with solvent
• The ligand’s synthetic yield

Correct Answer: The closeness of predicted pose to the experimentally observed binding mode

Q10. Which approach is best suited when no experimental structure of the target protein is available?

• Homology (comparative) modeling based on a related template structure
• Direct molecular docking without a protein model
• Assume the protein is rigid and use ligand-only methods
• Only use trial-and-error wet-lab screening

Correct Answer: Homology (comparative) modeling based on a related template structure

Q11. What is a pharmacophore model?

• An abstract representation of essential steric and electronic features required for molecular recognition
• A 3D printed model of the receptor binding site
• A chromatographic method for separating enantiomers
• A statistical test for clinical data

Correct Answer: An abstract representation of essential steric and electronic features required for molecular recognition

Q12. Which fingerprint and similarity metric pair is widely used for ligand-based virtual screening?

• ECFP (circular fingerprint) with Tanimoto coefficient
• Chromatogram fingerprint with Pearson correlation
• X-ray fingerprint with Euclidean distance
• MS spectra fingerprint with Spearman rank

Correct Answer: ECFP (circular fingerprint) with Tanimoto coefficient

Q13. Which simulation technique explicitly samples conformational dynamics and solvent effects over time?

• Molecular dynamics (MD) simulations
• Rigid-body docking with a single conformation
• Simple 2D QSAR regression
• High-throughput biochemical screening

Correct Answer: Molecular dynamics (MD) simulations

Q14. In free-energy perturbation (FEP) calculations, what is typically estimated?

• Relative binding free energy difference between chemically similar ligands
• Absolute pKa of an unrelated buffer component
• Molecular weight of the target protein
• Solvent dielectric constant at high pressure

Correct Answer: Relative binding free energy difference between chemically similar ligands

Q15. Why are water molecules sometimes explicitly included in docking?

• Because structural waters can mediate key hydrogen bonds and influence binding affinity
• Because water increases the resolution of X-ray data
• Because water always destabilizes ligand binding and must be present
• Because water molecules are required to compute molecular weight

Correct Answer: Because structural waters can mediate key hydrogen bonds and influence binding affinity

Q16. What is fragment-based drug design (FBDD)?

• An approach that screens small, low-complexity fragments and grows or links them to create higher-affinity ligands
• A method to fragment proteins into peptides for synthesis
• A way to break drug patents into smaller claims
• Screening only large macrocyclic compounds for activity

Correct Answer: An approach that screens small, low-complexity fragments and grows or links them to create higher-affinity ligands

Q17. Which of the following is a common limitation of docking scoring functions?

• Poor treatment of receptor entropy and solvent-mediated effects
• They always predict exact experimental IC50 values
• They require no parameterization for metal ions
• They cannot be used for any small molecule under 200 Da

Correct Answer: Poor treatment of receptor entropy and solvent-mediated effects

Q18. Which algorithmic strategy is frequently used to sample ligand conformations during docking?

• Genetic algorithms, Monte Carlo, and systematic torsion driving
• Simple linear regression of atomic coordinates
• Manual drawing of bonds on paper
• Direct measurement of binding energy in a spectrometer

Correct Answer: Genetic algorithms, Monte Carlo, and systematic torsion driving

Q19. In cheminformatics, what does the Lipinski “Rule of Five” primarily predict?

• Oral bioavailability likelihood based on simple molecular properties
• Intrinsic fluorescence of a compound
• Extent of hydrogen-deuterium exchange in mass spectrometry
• Best crystallization conditions for X-ray studies

Correct Answer: Oral bioavailability likelihood based on simple molecular properties

Q20. What is consensus scoring in virtual screening?

• Combining multiple scoring functions and/or docking methods to improve hit selection reliability
• Using a single scoring function exclusively for all targets
• Scoring only the largest compound in a library
• Eliminating all water molecules prior to docking

Correct Answer: Combining multiple scoring functions and/or docking methods to improve hit selection reliability

Download