Docking techniques in drug design are computational approaches used to predict how small molecules bind to biological targets, crucial for B. Pharm students learning rational drug discovery. This concise overview covers molecular docking fundamentals—ligand–receptor interactions, pose prediction, scoring functions, sampling algorithms, virtual screening, and structure-based drug design—while emphasizing practical aspects like protein and ligand preparation, solvent and ion effects, flexible docking, validation metrics (RMSD, enrichment) and post-docking refinement (rescoring, MM-PBSA). Understanding these concepts helps link in silico predictions to experimental assays, improving hit identification and lead optimization strategies. Now let’s test your knowledge with 30 MCQs on this topic.
Q1. What is the primary goal of molecular docking in drug design?
- To determine the metabolic stability of a drug candidate
- To predict the preferred orientation of a ligand when bound to a target
- To measure in vivo toxicity of compounds
- To calculate the pharmacokinetic profile of a molecule
Correct Answer: To predict the preferred orientation of a ligand when bound to a target
Q2. Which term describes the numerical estimate used to rank ligand poses by predicted binding strength?
- Pharmacophore
- Scoring function
- Force field parameter
- Hydrophobicity index
Correct Answer: Scoring function
Q3. Which scoring function type uses experimentally derived interaction energies and statistical potentials?
- Empirical scoring function
- Force-field based scoring function
- Knowledge-based (statistical) scoring function
- Quantum mechanical scoring
Correct Answer: Knowledge-based (statistical) scoring function
Q4. What does RMSD measure in docking validation?
- Root mean square deviation between predicted and experimental ligand poses
- Relative molecular solubility dispersion
- Rate of molecular synthesis deviation
- Receptor melting stability difference
Correct Answer: Root mean square deviation between predicted and experimental ligand poses
Q5. Which RMSD threshold is commonly used to consider a docking pose as correctly predicted?
- >5.0 Å
- 3.0–5.0 Å
- 2.0 Å or less
- 10.0 Å
Correct Answer: 2.0 Å or less
Q6. What is “induced fit” in the context of docking?
- A method where water molecules are ignored
- Flexibility of both ligand and receptor leading to conformational changes upon binding
- Docking that assumes rigid receptor and rigid ligand
- A scoring function that uses only hydrophobic contacts
Correct Answer: Flexibility of both ligand and receptor leading to conformational changes upon binding
Q7. Which search algorithm is stochastic and mimics biological evolution to explore conformational space?
- Systematic grid search
- Genetic algorithm
- Deterministic exhaustive search
- Linear regression
Correct Answer: Genetic algorithm
Q8. What is virtual screening in drug discovery?
- Experimental testing of compounds on cell cultures
- Computational screening of large libraries to identify potential binders
- Measuring binding affinities using calorimetry
- Synthesizing new compounds based on a scaffold
Correct Answer: Computational screening of large libraries to identify potential binders
Q9. Which of the following is a limitation of docking?
- It always predicts absolute binding free energy accurately
- It cannot sample ligand conformations
- Scoring functions may poorly rank true binders and false positives
- It replaces the need for experimental validation
Correct Answer: Scoring functions may poorly rank true binders and false positives
Q10. What is the purpose of receptor and ligand preparation before docking?
- To add irrelevant atoms for complexity
- To ensure correct protonation states, tautomers, and removal of artifacts
- To randomly alter sequences for variability
- To increase molecular weight artificially
Correct Answer: To ensure correct protonation states, tautomers, and removal of artifacts
Q11. What is consensus scoring?
- Using multiple scoring functions to improve ranking reliability
- Scoring only by hydrophobic contacts
- Applying a single force-field score repeatedly
- Discarding scores and using visual inspection only
Correct Answer: Using multiple scoring functions to improve ranking reliability
Q12. Which post-docking method refines binding free energy using continuum solvent models?
- MM-PBSA or MM-GBSA
- Simple docking score averaging
- Hydrophobicity mapping
- Ligand-based pharmacophore modeling
Correct Answer: MM-PBSA or MM-GBSA
Q13. What role do conserved water molecules sometimes play in docking?
- They always reduce binding affinity
- They can mediate key hydrogen bonds between ligand and receptor
- They are irrelevant and should always be removed
- They convert covalent interactions to noncovalent ones
Correct Answer: They can mediate key hydrogen bonds between ligand and receptor
Q14. What is blind docking?
- Docking without considering solvent effects
- Docking when the binding site is unknown or entire protein surface is searched
- Docking only for peptides
- Docking with quantum mechanics for all atoms
Correct Answer: Docking when the binding site is unknown or entire protein surface is searched
Q15. Which metric evaluates how well active compounds are separated from decoys in virtual screening?
- RMSD
- Enrichment factor or ROC-AUC
- pKa value
- LogP
Correct Answer: Enrichment factor or ROC-AUC
Q16. Which docking approach is most appropriate for fragment-based lead discovery?
- Large rigid-body docking only
- High-throughput fragment docking with flexible pocket sampling
- Ignoring protein flexibility altogether
- Only pharmacokinetic modeling
Correct Answer: High-throughput fragment docking with flexible pocket sampling
Q17. What is the typical unit used by many docking scores that estimate binding energy?
- moles per liter
- kcal/mol
- nanometers
- percent inhibition
Correct Answer: kcal/mol
Q18. Which factor must be carefully considered when docking metalloproteins?
- Presence and coordination geometry of metal ions
- Only ligand chirality matters
- Metal atoms can be ignored as inert
- Scoring functions automatically handle metals perfectly
Correct Answer: Presence and coordination geometry of metal ions
Q19. Why is tautomer and protonation state important in docking?
- They do not influence hydrogen bonding
- They determine charge distribution and hydrogen-bonding patterns affecting binding
- They only affect solubility, not binding
- They are fixed and do not vary in physiological pH
Correct Answer: They determine charge distribution and hydrogen-bonding patterns affecting binding
Q20. What is a decoy set in virtual screening validation?
- Set of highly active compounds only
- Non-binder molecules with similar physicochemical properties used to test specificity
- Random proteins used for cross-docking
- Set of water molecules placed in the binding site
Correct Answer: Non-binder molecules with similar physicochemical properties used to test specificity
Q21. Which method allows explicit sampling of receptor side-chain flexibility during docking?
- Rigid receptor docking
- Flexible side-chain docking or induced-fit protocols
- Ignoring side chains completely
- Only using scoring function adjustments
Correct Answer: Flexible side-chain docking or induced-fit protocols
Q22. What is rescoring in a docking workflow?
- Discarding all docking results
- Applying a more accurate or alternative scoring method to top-ranked poses
- Automatically synthesizing the top ligands
- Reducing the size of the ligand library arbitrarily
Correct Answer: Applying a more accurate or alternative scoring method to top-ranked poses
Q23. How does consensus docking improve hit selection?
- By combining results from different docking programs and scores to reduce false positives
- By ignoring experimental data entirely
- By using only one scoring function repeatedly
- By increasing the number of decoys
Correct Answer: By combining results from different docking programs and scores to reduce false positives
Q24. Which of the following best describes covalent docking?
- Docking that only predicts noncovalent interactions
- Modeling the formation of a covalent bond between ligand and target reactive residue
- Docking that ignores reactive residues
- Docking limited to nucleic acids
Correct Answer: Modeling the formation of a covalent bond between ligand and target reactive residue
Q25. What does ligand efficiency (LE) normalize in lead optimization?
- Binding energy per heavy atom to compare potency relative to size
- Solubility per polar surface area
- Metabolic clearance per dose
- LD50 per kilogram
Correct Answer: Binding energy per heavy atom to compare potency relative to size
Q26. Which software feature accelerates docking by precomputing potential energy grids for the receptor?
- Grid-based scoring
- Manual energy calculation
- Quantum cluster expansion
- Experimental X-ray refinement
Correct Answer: Grid-based scoring
Q27. How can homology models be used in docking when crystallographic structures are unavailable?
- They cannot be used at all
- As approximate receptor structures for docking after careful validation and refinement
- Only for small peptides, not small molecules
- They replace the need for protein preparation
Correct Answer: As approximate receptor structures for docking after careful validation and refinement
Q28. What is the main advantage of fragment docking followed by fragment growing or linking?
- Fragments always show high in vivo potency
- It explores binding hotspots and enables efficient optimization of small cores
- It replaces the need for binding assays
- Fragments avoid the need for scoring functions
Correct Answer: It explores binding hotspots and enables efficient optimization of small cores
Q29. Which of the following best describes enrichment factor in virtual screening?
- Ratio measuring how much better a virtual screen retrieves actives compared to random selection
- Measurement of ligand solubility enhancement
- Difference between docking poses
- Number of rotatable bonds in a ligand
Correct Answer: Ratio measuring how much better a virtual screen retrieves actives compared to random selection
Q30. After docking, which experimental technique is most commonly used to validate predicted binders?
- In silico ADMET prediction only
- Biophysical assays such as SPR, ITC, or enzyme inhibition assays
- Mass spectrometry of crude extracts only
- Visual inspection of protein crystals without binding data
Correct Answer: Biophysical assays such as SPR, ITC, or enzyme inhibition assays
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