Rational drug design: concepts and approaches MCQs With Answer

Introduction: Rational drug design combines biology, chemistry and computational tools to create molecules that selectively modulate biological targets. For M.Pharm students, mastering concepts such as structure-based and ligand-based approaches, pharmacophore modelling, QSAR, docking, fragment- and de novo design, and ADMET optimization is essential for modern drug discovery. This MCQ set focuses on core principles and practical strategies used to identify, optimize and evaluate lead compounds, emphasizing mechanistic understanding and decision-making steps during hit-to-lead progression. Each question tests theoretical knowledge and application skills needed for research, development and critical assessment of rational design workflows.

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

• SBDD requires knowledge of the target’s three-dimensional structure, while LBDD relies on information from known ligands
• SBDD only uses ligand information, whereas LBDD requires target structure
• SBDD is exclusively experimental chemistry, while LBDD is purely computational
• SBDD does not consider binding site geometry, but LBDD focuses on it

Correct Answer: SBDD requires knowledge of the target’s three-dimensional structure, while LBDD relies on information from known ligands

Q2. Which technique is most commonly used to determine a high-resolution three-dimensional structure of a protein target for SBDD?

• Nuclear magnetic resonance (NMR) spectroscopy
• X-ray crystallography
• Circular dichroism (CD) spectroscopy
• Ultracentrifugation

Correct Answer: X-ray crystallography

Q3. In QSAR modeling, what is the role of molecular descriptors?

• They are the experimental protocols for biological assays
• They numerically represent chemical structure properties used to correlate with biological activity
• They are visualization tools for protein-ligand complexes
• They are reagents used in synthesis of analogues

Correct Answer: They numerically represent chemical structure properties used to correlate with biological activity

Q4. Which statement best describes a pharmacophore model?

• A three-dimensional arrangement of steric and electronic features necessary for biological activity
• A single optimal ligand conformation that always binds to all targets
• A list of synthetic steps to produce a lead compound
• A metric for scoring docking poses only

Correct Answer: A three-dimensional arrangement of steric and electronic features necessary for biological activity

Q5. What is the primary advantage of fragment-based drug design (FBDD) over traditional high-throughput screening (HTS)?

• Fragments have higher molecular complexity and guarantee potency
• Fragments sample chemical space more efficiently and can be optimized into high-affinity leads
• Fragments eliminate the need for structural biology data
• Fragments always show complete ADMET profiles

Correct Answer: Fragments sample chemical space more efficiently and can be optimized into high-affinity leads

Q6. In molecular docking, what is the primary purpose of the scoring function?

• To synthesize the ligand in silico
• To predict the binding affinity and rank poses of ligands to the target
• To determine the crystal structure of the protein
• To simulate long-term dynamics of the protein-ligand complex

Correct Answer: To predict the binding affinity and rank poses of ligands to the target

Q7. Which concept explains the structural changes a protein undergoes upon ligand binding to achieve optimal fit?

• Isoelectric focusing
• Induced fit
• Hard-sphere packing
• Static lock-and-key only

Correct Answer: Induced fit

Q8. Bioisosteric replacement in lead optimization is primarily used to:

• Increase the size of a molecule without changing activity
• Replace a problematic functional group with another to retain activity while improving properties
• Completely change the scaffold to a new unrelated structure
• Only improve the color and odor of a compound

Correct Answer: Replace a problematic functional group with another to retain activity while improving properties

Q9. Which descriptor is commonly used in Lipinski’s Rule of Five to predict oral bioavailability?

• Number of stereocenters
• Partition coefficient (logP)
• Boiling point
• Optical rotation

Correct Answer: Partition coefficient (logP)

Q10. What is the main goal of hit-to-lead optimization in drug discovery?

• To identify the therapeutic indication for the compound without further testing
• To improve potency, selectivity, and drug-like properties of initial hits to produce viable leads
• To immediately proceed to Phase III clinical trials
• To scale up synthesis for commercial production

Correct Answer: To improve potency, selectivity, and drug-like properties of initial hits to produce viable leads

Q11. Which computational technique is best suited to study the time-dependent conformational flexibility of a protein-ligand complex?

• 2D-QSAR
• Molecular dynamics (MD) simulation
• Ligand-based pharmacophore mapping only
• Thin-layer chromatography

Correct Answer: Molecular dynamics (MD) simulation

Q12. What is “scaffold hopping” in medicinal chemistry?

• Replacing a lead’s core framework with a different scaffold to retain activity but change properties
• Moving molecules between different labs
• Increasing the molecular weight by adding rings to the scaffold
• Converting a small molecule into a peptide

Correct Answer: Replacing a lead’s core framework with a different scaffold to retain activity but change properties

Q13. Which of the following best describes a de novo design approach?

• Designing new ligands from scratch within a binding site using building blocks and optimization algorithms
• Only optimizing existing marketed drugs
• Using random combinatorial chemistry without structure information
• Extracting natural products without modification

Correct Answer: Designing new ligands from scratch within a binding site using building blocks and optimization algorithms

Q14. Which parameter derived from free energy perturbation (FEP) or MM-PBSA is most directly related to ligand binding strength?

• Binding free energy (ΔGbind)
• Melting temperature of the protein
• UV absorption maximum
• Retention time in HPLC

Correct Answer: Binding free energy (ΔGbind)

Q15. What is the main limitation of traditional docking predictions that scoring functions often fail to address?

• Lack of ability to rank ligands at all
• Limited treatment of protein flexibility and solvation effects leading to inaccurate affinity estimates
• Inability to handle ligands with heteroatoms
• Docking cannot generate any binding poses

Correct Answer: Limited treatment of protein flexibility and solvation effects leading to inaccurate affinity estimates

Q16. Which approach integrates absorption, distribution, metabolism, excretion and toxicity predictions early in design to reduce attrition?

• Lead optimization ignoring ADMET
• In silico ADMET and physicochemical profiling
• Only in vitro potency screening
• Random library synthesis

Correct Answer: In silico ADMET and physicochemical profiling

Q17. In ligand-based virtual screening, which method uses a statistical model relating multiple molecular descriptors to activity?

• Docking into a protein crystal structure
• QSAR modeling
• Protein homology modeling
• Fragment merging without descriptors

Correct Answer: QSAR modeling

Q18. Homology modeling is most appropriate when:

• A high-resolution structure for the target is unavailable but a related protein structure exists
• The exact ligand-binding thermodynamics are known experimentally
• Only small molecules with known metabolism are used
• No sequence data for the target is available

Correct Answer: A high-resolution structure for the target is unavailable but a related protein structure exists

Q19. Which of the following strategies can improve selectivity of a lead compound for its intended target over homologous proteins?

• Exploit unique residue differences in the target binding site during design
• Increase overall lipophilicity indiscriminately
• Decrease molecular rigidity to allow multiple binding modes
• Ignore structure-activity relationships (SAR)

Correct Answer: Exploit unique residue differences in the target binding site during design

Q20. Which metric is commonly used to quantify ligand efficiency by normalizing potency to molecular size during lead optimization?

• LogP only
• Ligand efficiency (LE), e.g., ΔGbind per heavy atom
• Boiling point per molecular weight
• Retention factor in thin-layer chromatography

Correct Answer: Ligand efficiency (LE), e.g., ΔGbind per heavy atom

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