De novo drug design and fragment-based approaches MCQs With Answer

Introduction: De novo drug design and fragment-based approaches MCQs With Answer is a focused quiz set tailored for M.Pharm students studying MPC 203T Computer Aided Drug Design. This collection emphasizes conceptual depth and practical application, covering structure-based and ligand-based de novo strategies, fragment screening techniques, fragment growing/linking/merging, scoring and synthetic feasibility, and experimental validation methods (X-ray, NMR, SPR, ITC). Questions are designed to reinforce understanding of algorithms, workflows, rules (e.g., Rule of Three), and optimization challenges encountered during fragment-to-lead progression. Use these MCQs to test knowledge, prepare for exams, and bridge computational theory with real-world lead discovery practice.

Q1. What is the primary distinction between de novo drug design and traditional virtual screening?

• De novo designs new molecular structures atom-by-atom or fragment-by-fragment, while virtual screening evaluates existing compound libraries for fit to a target
• De novo relies exclusively on ligand information, while virtual screening uses only protein structures
• Virtual screening always produces more synthetically feasible molecules than de novo
• De novo uses only quantum mechanics whereas virtual screening uses only molecular mechanics

Correct Answer: De novo designs new molecular structures atom-by-atom or fragment-by-fragment, while virtual screening evaluates existing compound libraries for fit to a target

Q2. In fragment-based drug discovery (FBDD), what is the Rule of Three commonly used to filter fragments?

• MW ≤ 300, LogP ≤ 3, HBD ≤ 3
• MW ≤ 250, clogP ≤ 3, HBA ≤ 3, HBD ≤ 3, Rotatable bonds ≤ 3
• MW ≤ 300, clogP ≤ 5, HBD ≤ 5
• MW ≤ 250, clogP ≤ 3, HBA ≤ 3, HBD ≤ 3, Rotatable bonds ≤ 3

Correct Answer: MW ≤ 250, clogP ≤ 3, HBA ≤ 3, HBD ≤ 3, Rotatable bonds ≤ 3

Q3. Which experimental technique is most sensitive for detecting very weak fragment-target interactions (millimolar to micromolar)?

• Surface Plasmon Resonance (SPR)
• X-ray crystallography
• Nuclear Magnetic Resonance (NMR)
• High-throughput fluorescence assay

Correct Answer: Nuclear Magnetic Resonance (NMR)

Q4. In structure-based de novo design, what is a commonly used strategy to grow fragments into larger molecules?

• Fragment growing by sequential addition of chemically compatible fragments into unoccupied pockets guided by scoring functions
• Randomly concatenating fragments from a library without considering the binding site
• Only increasing hydrophobic surface area to improve binding affinity
• Replacing polar groups with fluorine to increase lipophilicity

Correct Answer: Fragment growing by sequential addition of chemically compatible fragments into unoccupied pockets guided by scoring functions

Q5. Which computational method specifically evaluates synthetic accessibility and suggests retrosynthetic disconnections during de novo design?

• HotSpot mapping
• Retrosynthetic analysis engines or synthetic feasibility scoring tools (e.g., retrosynthesis planners)
• Pharmacophore modeling
• Classical molecular dynamics without reaction rules

Correct Answer: Retrosynthetic analysis engines or synthetic feasibility scoring tools (e.g., retrosynthesis planners)

Q6. What is the main advantage of fragment merging compared to fragment linking?

• Merging combines overlapping fragment pharmacophores into a single scaffold, often minimizing linker design and preserving binding efficiency
• Merging always yields higher molecular weight compounds than linking
• Merging requires no structural information about the binding site
• Merging increases the number of rotatable bonds more than linking

Correct Answer: Merging combines overlapping fragment pharmacophores into a single scaffold, often minimizing linker design and preserving binding efficiency

Q7. Which scoring challenge is particularly acute in fragment-based de novo design due to fragment small size?

• Overestimation of entropic penalty only
• Poor discrimination of weak binders because binding energy contributions are small and scoring functions are less sensitive at low affinity
• Scoring functions do not consider hydrogen bonds
• Inability to compute molecular weight

Correct Answer: Poor discrimination of weak binders because binding energy contributions are small and scoring functions are less sensitive at low affinity

Q8. Which approach is described by generating many candidate molecules around a binding site using fragment libraries and an algorithm to place, grow, and score fragments?

• Ligand-based QSAR
• De novo structure-based design (fragment-based de novo)
• High throughput screening
• Classical pharmacokinetic modelling

Correct Answer: De novo structure-based design (fragment-based de novo)

Q9. What is a ‘hotspot’ in the context of fragment-based design?

• A highly flexible region of the protein that cannot bind small molecules
• A region of the binding site with favorable physicochemical properties that contributes disproportionately to binding energy and is ideal for fragment placement
• A thermodynamically unfavorable cavity on the protein surface
• A region defined only by solvent-exposed charged residues

Correct Answer: A region of the binding site with favorable physicochemical properties that contributes disproportionately to binding energy and is ideal for fragment placement

Q10. Which computational technique helps prioritize fragment growth vectors by sampling conformations and estimating free energy changes?

• Molecular dynamics (MD) and free energy perturbation (FEP) or alchemical calculations
• 2D-QSAR without structure
• Simple rule-based Lipinski filters only
• Basic geometric fingerprint matching without energetics

Correct Answer: Molecular dynamics (MD) and free energy perturbation (FEP) or alchemical calculations

Q11. In fragment linking, what is a critical geometric requirement to achieve a successful linked molecule?

• The two fragments must be in adjacent but non-overlapping binding pockets without any spatial constraint
• The two fragment exit vectors must have compatible distance and orientation so a chemically reasonable linker can connect them without disrupting interactions
• The fragments should be identical in structure
• Linker length should always be at least 15 heavy atoms

Correct Answer: The two fragment exit vectors must have compatible distance and orientation so a chemically reasonable linker can connect them without disrupting interactions

Q12. Which property is typically optimized during fragment-to-lead progression besides potency?

• Only molecular weight, ignoring ADME
• ADME/Toxicity profiles, selectivity, and synthetic tractability in addition to potency
• Only rotatable bond count
• Number of fragments used irrespective of pharmacology

Correct Answer: ADME/Toxicity profiles, selectivity, and synthetic tractability in addition to potency

Q13. Which software approach is known for de novo placement of fragments using graph-based or rule-driven assembly in a protein pocket?

• LUDI, SPROUT, and LEA3D style algorithms that assemble fragments in the binding site
• Only BLAST sequence alignment tools
• Traditional empirical force-field parameterization software exclusively
• 2D cheminformatics for predicting boiling points

Correct Answer: LUDI, SPROUT, and LEA3D style algorithms that assemble fragments in the binding site

Q14. When using X-ray crystallography for fragment screening, what advantage does it provide over biochemical assays?

• X-ray gives direct structural evidence of fragment binding mode and orientation, enabling rational design decisions
• X-ray is faster and higher throughput than all biochemical assays
• X-ray cannot detect fragment binding at high concentrations
• X-ray provides direct measurement of in vivo efficacy

Correct Answer: X-ray gives direct structural evidence of fragment binding mode and orientation, enabling rational design decisions

Q15. Which descriptor pair is most commonly evaluated to maintain fragment-like characteristics during optimization?

• Molecular weight and cLogP
• Topological polar surface area (TPSA) only
• Number of rings only
• UV absorbance and melting point

Correct Answer: Molecular weight and cLogP

Q16. What is the principal risk when aggressively merging fragments to improve binding affinity?

• Creating molecules with improved water solubility only
• Generating high molecular weight, high lipophilicity structures with poor ADME and decreased ligand efficiency
• Automatically reducing potency
• Eliminating all hydrogen bond donors

Correct Answer: Generating high molecular weight, high lipophilicity structures with poor ADME and decreased ligand efficiency

Q17. Which metric is particularly useful to compare potency relative to molecular size in fragment-based design?

• Ligand Efficiency (LE), defined as binding energy per heavy atom or per molecular weight unit
• Only IC50 value without normalization
• Number of aromatic rings
• Circular dichroism spectrum

Correct Answer: Ligand Efficiency (LE), defined as binding energy per heavy atom or per molecular weight unit

Q18. In a de novo algorithm that uses pharmacophore constraints, what is the role of the pharmacophore?

• To provide 2D fingerprints for clustering only
• To enforce spatial arrangement of essential interaction features (H-bond donors/acceptors, hydrophobes, charges) guiding placement and growth of fragments
• To replace quantum mechanical calculations completely
• To limit fragment growth to increasing aromaticity only

Correct Answer: To enforce spatial arrangement of essential interaction features (H-bond donors/acceptors, hydrophobes, charges) guiding placement and growth of fragments

Q19. Which challenge is reduced by using fragment libraries instead of screening large lead-like libraries?

• Reduced chemical diversity
• Lower hit rates and unclear binding modes
• Sampling complexity is reduced because small fragments cover chemical space more efficiently and can explore diverse interactions with fewer compounds
• Inability to detect weak binders

Correct Answer: Sampling complexity is reduced because small fragments cover chemical space more efficiently and can explore diverse interactions with fewer compounds

Q20. Which combined computational-experimental workflow step is essential to validate computationally designed fragment-grown molecules?

• Skip experimental validation if scoring is high
• Synthesize prioritized compounds followed by biophysical confirmation (e.g., X-ray, NMR, SPR) and iterative optimization based on structural data
• Only increase in silico docking score is required for lead nomination
• Directly advance to animal efficacy studies without biophysical profiling

Correct Answer: Synthesize prioritized compounds followed by biophysical confirmation (e.g., X-ray, NMR, SPR) and iterative optimization based on structural data

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