Structure-based drug design methodologies MCQs With Answer

Introduction: Structure-based drug design (SBDD) integrates three-dimensional structural information of biological targets with computational and experimental methods to design potent, selective drug candidates. For M.Pharm students, mastering SBDD methodologies — including X-ray crystallography, cryo-EM, NMR, homology modeling, molecular docking, fragment-based design, molecular dynamics, and free energy calculations — is essential for rational lead discovery and optimization. This set of MCQs focuses on core principles, practical techniques, interpretation of structural data, and advanced computational strategies used in SBDD. Questions are designed to deepen conceptual understanding and prepare students for applying structure-guided approaches in research and pharmaceutical development.

Q1. Which experimental technique traditionally provides the highest-resolution atomic coordinates for protein–ligand complexes used in structure-based drug design?

• X-ray crystallography
• Cryo-electron microscopy (cryo-EM)
• Nuclear magnetic resonance (NMR) spectroscopy
• Surface plasmon resonance (SPR)

Correct Answer: X-ray crystallography

Q2. Which structural biology method has recently become more useful for large macromolecular complexes and often complements X-ray data in SBDD?

• Nuclear Overhauser Effect spectroscopy
• Small-angle X-ray scattering (SAXS)
• Cryo-electron microscopy (cryo-EM)
• Isothermal titration calorimetry (ITC)

Correct Answer: Cryo-electron microscopy (cryo-EM)

Q3. What is the central principle of fragment-based drug design (FBDD)?

• Screen large libraries of drug-like molecules to find high-affinity binders
• Start with low molecular-weight fragments that bind weakly and grow or merge them into higher-affinity leads
• Use only covalent modifiers to ensure irreversible binding
• Design ligands solely based on ligand-based QSAR without structural data

Correct Answer: Start with low molecular-weight fragments that bind weakly and grow or merge them into higher-affinity leads

Q4. Which concept describes the protein’s conformational change upon ligand binding often considered in SBDD?

• Lock-and-key model
• Induced fit model
• Passive diffusion model
• Allosteric blockade model

Correct Answer: Induced fit model

Q5. Which categories correctly describe common classes of docking scoring functions?

• Empirical, knowledge-based, and force-field-based scoring functions
• Hydrophobic, hydrophilic, and amphipathic scoring functions
• Primary, secondary, and tertiary scoring functions
• Pharmacokinetic, pharmacodynamic, and toxicological scoring functions

Correct Answer: Empirical, knowledge-based, and force-field-based scoring functions

Q6. What does the MM-PBSA method estimate in the context of SBDD?

• Quantum-level electronic transitions in a ligand
• End-point binding free energy combining molecular mechanics and continuum solvent models
• Protein tertiary structure from sequence alone
• Maximum parsimony alignment score for ligands

Correct Answer: End-point binding free energy combining molecular mechanics and continuum solvent models

Q7. What is the main purpose of ensemble docking in accounting for target flexibility?

• To dock ligands into multiple target conformations obtained from experiments or MD simulations
• To perform docking on multiple ligand tautomers only
• To average ligand properties across different protonation states only
• To restrict docking to a single high-energy conformation

Correct Answer: To dock ligands into multiple target conformations obtained from experiments or MD simulations

Q8. How can conserved water molecules in a binding site influence structure-based ligand design?

• They are always ignored because waters never mediate interactions
• They can mediate hydrogen-bond networks and be exploited or displaced to gain affinity
• They only decrease ligand solubility and are irrelevant for binding
• They mandate the use of covalent inhibitors exclusively

Correct Answer: They can mediate hydrogen-bond networks and be exploited or displaced to gain affinity

Q9. When building a homology model for SBDD, what minimum sequence identity to the template is generally considered to yield a reasonably accurate backbone model?

• Less than 10% sequence identity
• About 20% sequence identity
• Greater than approximately 30% sequence identity
• Exactly 100% sequence identity is mandatory

Correct Answer: Greater than approximately 30% sequence identity

Q10. In docking validation, which RMSD value between predicted and experimental ligand poses is commonly used as a threshold indicating a successful pose prediction?

• RMSD > 5.0 Å
• RMSD around 3.5–4.5 Å
• RMSD < 2.0 Å
• RMSD exactly equal to 2.5 Å

Correct Answer: RMSD < 2.0 Å

Q11. What does the metric ‘ligand efficiency’ represent in SBDD?

• Binding affinity normalized per heavy (non-hydrogen) atom of the ligand
• Total molecular weight divided by logP
• Number of rotatable bonds per hydrogen bond
• Percentage of polar surface area that is solvent exposed

Correct Answer: Binding affinity normalized per heavy (non-hydrogen) atom of the ligand

Q12. Which experimental techniques are commonly used for fragment screening in FBDD?

• X-ray crystallography, NMR spectroscopy, surface plasmon resonance (SPR), and thermal shift assays
• Only high-throughput cell-based phenotypic assays
• Gas chromatography and mass spectrometry exclusively
• Electrophoretic mobility shift assays only

Correct Answer: X-ray crystallography, NMR spectroscopy, surface plasmon resonance (SPR), and thermal shift assays

Q13. What does a structure-based pharmacophore model encode?

• Only the ligand’s 1D SMILES string
• The 3D arrangement of essential interaction features (e.g., H-bond donors/acceptors, hydrophobes) required for binding
• The metabolic stability of a compound in the liver
• The synthetic route for ligand synthesis

Correct Answer: The 3D arrangement of essential interaction features (e.g., H-bond donors/acceptors, hydrophobes) required for binding

Q14. What is a key design consideration when developing covalent inhibitors using SBDD?

• Choosing a non-reactive scaffold that forms only weak van der Waals contacts
• Selecting an appropriate electrophilic warhead that targets a nucleophilic residue in a non-conserved site
• Ensuring the inhibitor is completely metabolically inert regardless of reactivity
• Avoiding any structural information about the nucleophile’s environment

Correct Answer: Selecting an appropriate electrophilic warhead that targets a nucleophilic residue in a non-conserved site

Q15. For relative binding free energy calculations in lead optimization of congeneric series, which method is considered most rigorous though computationally intensive?

• Empirical scoring by glide score alone
• Free energy perturbation (FEP) or thermodynamic integration (TI)
• Simple docking rank-ordering without rescoring
• Ligand-based 2D fingerprint similarity

Correct Answer: Free energy perturbation (FEP) or thermodynamic integration (TI)

Q16. What is the main advantage of consensus scoring in virtual screening?

• It always identifies the single best ligand without false positives
• It reduces false positives by combining rankings from multiple scoring functions
• It eliminates the need for any experimental validation
• It guarantees exact binding free energy predictions

Correct Answer: It reduces false positives by combining rankings from multiple scoring functions

Q17. Which experimental approach is commonly used to map energetic “hot spots” in protein–protein or protein–ligand interfaces for SBDD?

• Alanine-scanning mutagenesis coupled with binding assays
• Thin-layer chromatography of ligands
• Gas-phase ion mobility spectrometry
• Western blotting of whole-cell lysates

Correct Answer: Alanine-scanning mutagenesis coupled with binding assays

Q18. Why are allosteric binding sites attractive targets in structure-based drug design?

• They always produce irreversible binding and toxicology issues
• They are never conserved and thus cannot be targeted selectively
• They can offer improved selectivity, novel mechanisms, and reduced competition with endogenous ligands
• They only bind large peptides and are unsuitable for small molecules

Correct Answer: They can offer improved selectivity, novel mechanisms, and reduced competition with endogenous ligands

Q19. Which tool or plot is most commonly used to validate backbone dihedral angles in protein structural models?

• Ramachandran plot
• Boltzmann plot
• Lineweaver–Burk plot
• Thermogravimetric analysis plot

Correct Answer: Ramachandran plot

Q20. In structure-based lead optimization, which combination of properties is typically balanced to progress a compound toward a preclinical candidate?

• Only increasing molecular weight and lipophilicity without regard to ADME
• Improving potency while optimizing ADME, selectivity, and minimizing toxicity
• Reducing potency to lower off-target effects regardless of ADME
• Focusing solely on synthetic ease and ignoring biological activity

Correct Answer: Improving potency while optimizing ADME, selectivity, and minimizing toxicity

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