Introduction: Rational drug design integrates biological target knowledge with computational and experimental tools to create effective therapeutics. Key approaches include structure-based drug design (SBDD), ligand-based drug design (LBDD), molecular docking, pharmacophore modeling, QSAR, virtual screening, fragment-based design, de novo design, homology modeling, and ADMET prediction. B. Pharm students should grasp concepts like lead identification, lead optimization, scoring functions, molecular dynamics, free energy methods, bioisosterism, and cheminformatics descriptors. Understanding these methods improves your ability to interpret drug discovery literature and design safer, potent molecules. Now let’s test your knowledge with 30 MCQs on this topic.
Q1. What is the primary principle of structure-based drug design (SBDD)?
- Designing drugs solely by modifying existing marketed drugs
- Using the three-dimensional structure of a biological target to design ligands
- Screening thousands of compounds experimentally without structural information
- Relying on traditional herbal remedies for lead discovery
Correct Answer: Using the three-dimensional structure of a biological target to design ligands
Q2. Which technique is central to ligand-based drug design (LBDD)?
- X-ray crystallography of the receptor
- Pharmacophore modeling and QSAR using known ligands
- Cryo-EM of the ligand-receptor complex
- Proteomics to discover new targets
Correct Answer: Pharmacophore modeling and QSAR using known ligands
Q3. Which method predicts binding poses and approximate affinities of small molecules to a target site?
- Molecular docking
- High performance liquid chromatography
- Gel electrophoresis
- Western blotting
Correct Answer: Molecular docking
Q4. What does QSAR (Quantitative Structure–Activity Relationship) primarily correlate?
- 3D protein fold with stability
- Chemical structure descriptors with biological activity
- Gene expression with toxicity
- Solubility with melting point
Correct Answer: Chemical structure descriptors with biological activity
Q5. Which technique helps when the target’s crystal structure is unavailable?
- Homology modeling to build a target model
- Direct mass spectrometry of the ligand
- NMR spectroscopy of the whole organism
- Thin-layer chromatography
Correct Answer: Homology modeling to build a target model
Q6. What is a pharmacophore?
- A type of chromatographic column
- An abstract arrangement of steric and electronic features necessary for biological activity
- A protein folding chaperone
- A synthetic route for lead optimization
Correct Answer: An abstract arrangement of steric and electronic features necessary for biological activity
Q7. Which approach is best for finding novel small fragments that bind weakly to a target?
- Fragment-based drug design (FBDD)
- High-throughput screening (HTS) of large compounds
- Proteomics profiling
- Classical medicinal chemistry without screening
Correct Answer: Fragment-based drug design (FBDD)
Q8. Virtual screening refers to:
- Computationally evaluating large libraries of compounds against a target
- Screening compounds using animal models
- Testing compounds in vitro using ELISA only
- Manual visual inspection of chemical structures
Correct Answer: Computationally evaluating large libraries of compounds against a target
Q9. Which parameter is NOT typically part of in silico ADMET prediction?
- Permeability
- Metabolic stability
- Maximal tolerated dose in humans (clinical)
- Plasma protein binding
Correct Answer: Maximal tolerated dose in humans (clinical)
Q10. What does the term ‘lead optimization’ involve?
- Scaling up manufacturing before biological testing
- Improving potency, selectivity, and ADMET of a lead compound
- Discarding leads and starting over
- Only performing toxicity tests on the lead
Correct Answer: Improving potency, selectivity, and ADMET of a lead compound
Q11. Which scoring function component often correlates best with binding affinity in docking?
- Electrostatic and van der Waals interaction terms
- Compound supplier reputation
- Number of rotatable bonds only
- Molecular color
Correct Answer: Electrostatic and van der Waals interaction terms
Q12. What is induced fit in the context of ligand binding?
- The ligand remains rigid while the solvent changes
- The receptor changes conformation upon ligand binding to accommodate it
- Ligand degradation during binding
- Protein aggregation during crystallization
Correct Answer: The receptor changes conformation upon ligand binding to accommodate it
Q13. Molecular dynamics (MD) simulations are used to:
- Predict long-term pharmacokinetics in humans directly
- Study conformational flexibility and stability of protein-ligand complexes
- Identify elemental composition of a drug
- Measure enzymatic activity in vitro
Correct Answer: Study conformational flexibility and stability of protein-ligand complexes
Q14. Free energy perturbation (FEP) methods are most useful for:
- Estimating relative binding free energies between similar ligands
- Sequencing bacterial genomes
- Measuring melting points of solids
- Visualizing protein crystals
Correct Answer: Estimating relative binding free energies between similar ligands
Q15. Which molecular property is emphasized by the Lipinski’s Rule of Five?
- Suitability for oral bioavailability
- Ability to cross the blood–brain barrier exclusively
- Intrinsic fluorescence
- Enzymatic turnover rate
Correct Answer: Suitability for oral bioavailability
Q16. What is scaffold hopping?
- Replacing a core molecular scaffold to find new chemotypes with similar activity
- Immediate clinical trials without preclinical tests
- Moving a laboratory to a different building
- Combining two approved drugs into a fixed-dose formulation
Correct Answer: Replacing a core molecular scaffold to find new chemotypes with similar activity
Q17. Which descriptor is commonly used in cheminformatics for molecular similarity searches?
- Topological fingerprints (e.g., ECFP)
- Thermal conductivity
- Protein molecular weight
- pH of the solvent
Correct Answer: Topological fingerprints (e.g., ECFP)
Q18. Bioisosteric replacement is applied to:
- Improve pharmacokinetic or safety properties while retaining activity
- Change the color of the compound
- Increase compound melting temperature only
- Eliminate all hydrogen bond donors
Correct Answer: Improve pharmacokinetic or safety properties while retaining activity
Q19. Which experimental technique provides high-resolution atomic structures used in SBDD?
- X-ray crystallography
- UV–Vis spectroscopy
- Infrared spectroscopy
- Particle size analysis
Correct Answer: X-ray crystallography
Q20. Ensemble docking addresses which limitation of single-structure docking?
- Accounting for receptor flexibility by using multiple conformations
- Reducing computational cost to zero
- Guaranteeing clinical efficacy
- Automatically synthesizing compounds in silico
Correct Answer: Accounting for receptor flexibility by using multiple conformations
Q21. What is the main advantage of fragment-based lead discovery over traditional HTS?
- Smaller libraries can explore chemical space more efficiently via high ligand efficiency
- Fragments are always orally active drugs
- Fragments eliminate the need for structure determination
- Fragments are cheaper to analyze by mass spectrometry only
Correct Answer: Smaller libraries can explore chemical space more efficiently via high ligand efficiency
Q22. MM-PBSA calculations are commonly used to:
- Estimate binding free energies from MD trajectories
- Design clinical trial protocols
- Predict chemical synthesis yields
- Measure blood pressure in vivo
Correct Answer: Estimate binding free energies from MD trajectories
Q23. Which of the following is a common limitation of docking scoring functions?
- They may poorly account for entropic and solvent effects
- They always predict exact in vivo potency
- They can measure toxicity directly
- They sequence DNA automatically
Correct Answer: They may poorly account for entropic and solvent effects
Q24. What role does homology modeling play in rational drug design?
- Provides a structural model of a target when an experimental structure is absent
- Directly measures clinical drug-response rates
- Predicts market demand for a drug
- Replaces the need for medicinal chemistry
Correct Answer: Provides a structural model of a target when an experimental structure is absent
Q25. Which in silico method helps identify water molecules important for ligand binding?
- Water mapping and hydration site analysis
- IR spectroscopy of solid samples
- UV titration
- Carbon dating
Correct Answer: Water mapping and hydration site analysis
Q26. De novo drug design refers to:
- Building novel ligand structures atom-by-atom or fragment-by-fragment using target information
- Replicating existing marketed drugs exactly
- Testing drugs only in traditional medicine systems
- Performing only ADMET tests on approved compounds
Correct Answer: Building novel ligand structures atom-by-atom or fragment-by-fragment using target information
Q27. Which metric helps compare potency relative to molecular size during lead selection?
- Ligand efficiency (LE)
- Boiling point
- Crystal packing density
- Optical rotation
Correct Answer: Ligand efficiency (LE)
Q28. What is the primary goal of target validation in drug discovery?
- Confirming that modulating the target affects disease-relevant biology
- Scaling up drug manufacturing
- Publishing a patent regardless of biology
- Measuring compound solubility only
Correct Answer: Confirming that modulating the target affects disease-relevant biology
Q29. Which technique can directly observe ligand binding and conformational changes in solution?
- Nuclear magnetic resonance (NMR) spectroscopy
- Gas chromatography
- Paper chromatography
- Colorimetric pH testing
Correct Answer: Nuclear magnetic resonance (NMR) spectroscopy
Q30. Which combination of in silico methods is most commonly used in an integrated lead discovery workflow?
- Virtual screening (docking), pharmacophore filtering, QSAR modeling, and ADMET prediction
- Only clinical trials without prior modeling
- Purely wet-lab synthesis with no computational input
- Random selection of molecules by visual inspection
Correct Answer: Virtual screening (docking), pharmacophore filtering, QSAR modeling, and ADMET prediction
I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.
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