De novo drug design principles MCQs With Answer

De novo drug design principles MCQs With Answer

This collection of 20 carefully curated multiple-choice questions is designed for M.Pharm students studying Principles of Drug Discovery. The quiz focuses on de novo drug design concepts, including structure- and ligand-based strategies, fragment growing and linking, scoring functions, sampling algorithms, ADMET and synthetic accessibility considerations, and integration with cheminformatics and machine learning. Each question targets core theoretical principles and practical challenges encountered during computer-aided design of novel scaffolds, aiming to deepen understanding of how chemical space is explored and optimized for potency, selectivity, and developability. Answers are provided to help self-assessment and guide further study.

Q1. In structure-based de novo design, which step is most critical for ensuring that generated molecules fit the binding site geometry accurately?

• Maximizing molecular weight to increase binding contacts
• Precise conformational sampling of the ligand and binding pocket
• Using only 2D pharmacophore features
• Ionic strength adjustment of the docking software

Correct Answer: Precise conformational sampling of the ligand and binding pocket

Q2. Fragment-based de novo design often uses fragment linking or fragment growing. What is a primary advantage of fragment linking over fragment growing?

• Linking avoids considering binding site water molecules
• Linking can recover high-affinity compounds by combining two validated fragment anchors
• Linking requires no consideration of synthetic feasibility
• Linking eliminates the need for scoring functions

Correct Answer: Linking can recover high-affinity compounds by combining two validated fragment anchors

Q3. Which scoring function component is most important when de novo designing to prioritize molecules with favorable desolvation and enthalpic interactions?

• Penalty for rotatable bonds
• Electrostatic and van der Waals interaction energy terms
• Synthetic accessibility score
• LogP prediction

Correct Answer: Electrostatic and van der Waals interaction energy terms

Q4. In de novo design, why is synthetic accessibility (SA) scoring incorporated into the objective function?

• To ensure molecules have the highest possible molecular weight
• To penalize structures unlikely to be synthesizable in practice
• To maximize conformational flexibility
• To replace the need for ADMET prediction

Correct Answer: To penalize structures unlikely to be synthesizable in practice

Q5. Which method is most appropriate when lacking a high-resolution protein structure but having multiple known active ligands?

• Structure-based de novo design using homology modeling only
• Ligand-based de novo design using pharmacophore and similarity-driven generation
• Fragment linking using the apo protein
• Rely exclusively on docking to an unrelated protein

Correct Answer: Ligand-based de novo design using pharmacophore and similarity-driven generation

Q6. In de novo generation, “scaffold hopping” primarily aims to:

• Increase the number of rotatable bonds
• Replace the core scaffold while retaining key pharmacophoric interactions to improve properties
• Reduce computational cost by using larger scaffolds
• Ensure molecules are more rigid irrespective of activity

Correct Answer: Replace the core scaffold while retaining key pharmacophoric interactions to improve properties

Q7. Which of the following describes a major risk of relying solely on docking scores during de novo design?

• Docking scores perfectly predict ADME properties
• Docking may misrank compounds due to scoring function limitations and neglect of entropic contributions
• Docking always accounts for induced-fit conformational changes accurately
• Docking eliminates the need for experimental validation

Correct Answer: Docking may misrank compounds due to scoring function limitations and neglect of entropic contributions

Q8. What role do explicit water molecules often play when included in de novo design for a binding site?

• Water molecules always destabilize ligand binding and should be removed
• They can mediate key hydrogen-bond networks and influence fragment placement and scoring
• They increase ligand lipophilicity artificially
• They are only relevant for covalent inhibitors

Correct Answer: They can mediate key hydrogen-bond networks and influence fragment placement and scoring

Q9. In multi-objective de novo optimization, Pareto front selection is used to:

• Rank compounds only by potency and ignore other properties
• Identify trade-offs among competing objectives (e.g., potency, toxicity, synthetic accessibility) without aggregating into a single score
• Guarantee the most synthetically accessible compound is selected
• Exclude any compounds with rotatable bonds

Correct Answer: Identify trade-offs among competing objectives (e.g., potency, toxicity, synthetic accessibility) without aggregating into a single score

Q10. Free energy perturbation (FEP) calculations in de novo design are most valuable for:

• Rapid virtual screening of millions of designs
• Accurately estimating relative binding free energies for closely related analogs to aid lead optimization
• Predicting synthetic pathways automatically
• Replacing all docking and scoring steps due to negligible computational cost

Correct Answer: Accurately estimating relative binding free energies for closely related analogs to aid lead optimization

Q11. Which concept refers to replacement of a functional group with another that retains biological activity but improves properties such as PK or safety?

• Fragment linking
• Bioisosterism
• Scaffold explosion
• Conformational locking

Correct Answer: Bioisosterism

Q12. When designing covalent inhibitors de novo, what additional consideration is essential compared to reversible ligand design?

• Only hydrophobic interactions matter
• Reactive warhead placement and selective reactivity toward the target nucleophile must be controlled to avoid off-target toxicity
• Covalent inhibitors do not require conformational sampling
• Scaffold diversity is unimportant

Correct Answer: Reactive warhead placement and selective reactivity toward the target nucleophile must be controlled to avoid off-target toxicity

Q13. In generative model–based de novo design (e.g., variational autoencoders or GANs), a major advantage is:

• Guaranteed synthetic feasibility of generated molecules
• Ability to sample novel chemotypes from learned chemical distributions and condition generation on desired properties
• No need for downstream validation or filtering
• Elimination of the need for experimental testing

Correct Answer: Ability to sample novel chemotypes from learned chemical distributions and condition generation on desired properties

Q14. Which metric best describes how well a de novo method enriches actives over decoys during virtual screening validation?

• Root-mean-square deviation (RMSD)
• Enrichment factor (EF) or ROC-AUC
• Synthetic accessibility score
• Number of rotatable bonds

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

Q15. How does conformational flexibility of the receptor complicate de novo design and what is a common approach to address it?

• Flexibility has no effect; always use a single rigid receptor
• It creates multiple possible binding site shapes; address by ensemble docking or induced-fit modeling to sample receptor conformations
• It prevents any computational scoring; therefore designs must be random
• It can be ignored if ligands are large

Correct Answer: It creates multiple possible binding site shapes; address by ensemble docking or induced-fit modeling to sample receptor conformations

Q16. In de novo workflows, why is early ADMET filtering beneficial?

• To increase molecular weight rapidly
• To reduce wasted effort on molecules likely to fail later due to poor absorption, metabolism, toxicity, or clearance
• To ensure all generated molecules are covalent inhibitors
• To guarantee perfect plasma protein binding profiles

Correct Answer: To reduce wasted effort on molecules likely to fail later due to poor absorption, metabolism, toxicity, or clearance

Q17. What is one limitation of fragment growing algorithms compared to expert medicinal chemists?

• They always produce synthetically trivial compounds
• They may propose chemically unstable or synthetically implausible linkers that a chemist would avoid
• They fully replace the need for retrosynthetic planning
• They automatically predict metabolic liabilities

Correct Answer: They may propose chemically unstable or synthetically implausible linkers that a chemist would avoid

Q18. Which strategy improves the diversity of generated compounds while maintaining activity hypotheses in de novo design?

• Strictly maximizing molecular weight
• Applying multiple pharmacophore constraints with allowed tolerant regions and scaffold hopping to explore alternative cores
• Eliminating all heteroatoms from designs
• Only using a single fragment as the exclusive starting point

Correct Answer: Applying multiple pharmacophore constraints with allowed tolerant regions and scaffold hopping to explore alternative cores

Q19. What is a main advantage of integrating retrosynthesis prediction into de novo generative pipelines?

• Retrosynthesis ensures generated molecules are perfectly nonpolar
• It provides an estimate of how practically synthesizable a proposal is and suggests feasible synthetic routes for prioritization
• It eliminates the need for experimental chemistry teams
• It guarantees favorable ADMET profiles

Correct Answer: It provides an estimate of how practically synthesizable a proposal is and suggests feasible synthetic routes for prioritization

Q20. When evaluating de novo designed macrocycles, what particular challenge must be considered compared with small flexible molecules?

• Macrocycles have no stereochemistry concerns
• Their conformational sampling and entropic penalties are complex, and ring-closing geometry can drastically affect binding thermodynamics
• Macrocycles are always permeable and require no ADME assessment
• Macrocycles simplify docking because rigidity is always high

Correct Answer: Their conformational sampling and entropic penalties are complex, and ring-closing geometry can drastically affect binding thermodynamics

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