Molecular modeling in drug design introduces computational tools that predict how small molecules interact with biological targets, helping B. Pharm students understand rational lead discovery and optimization. Key concepts include docking, molecular dynamics (MD), quantitative structure–activity relationships (QSAR), pharmacophore modeling, virtual screening, force fields, solvation models, and ADMET prediction. Practical skills cover homology modeling, conformational analysis, scoring functions, ligand efficiency metrics, and validation techniques like ROC and enrichment studies. This topic links theory to practice by explaining how in silico methods reduce experimental cost and guide medicinal chemistry decisions. ‘Now let’s test your knowledge with 30 MCQs on this topic.’
Q1. What is the primary goal of molecular docking in drug design?
- To synthesize new drug molecules in the lab
- To predict the preferred orientation and binding affinity of a ligand to a receptor
- To determine the toxicity of a compound in vivo
- To model protein secondary structure from sequence data
Correct Answer: To predict the preferred orientation and binding affinity of a ligand to a receptor
Q2. Which technique simulates atomic motions over time to study stability and conformational changes of protein–ligand complexes?
- Docking
- Pharmacophore mapping
- Molecular dynamics (MD) simulation
- QSAR regression
Correct Answer: Molecular dynamics (MD) simulation
Q3. QSAR models primarily relate which of the following to biological activity?
- Protein folding pathways
- Chemical descriptors of molecules (e.g., logP, molecular weight, electronic descriptors)
- Experimental animal behavior
- Crystallographic B-factors
Correct Answer: Chemical descriptors of molecules (e.g., logP, molecular weight, electronic descriptors)
Q4. Which force field component represents non-bonded electrostatic interactions between atoms?
- Bond stretch term
- Angle bend term
- Torsional (dihedral) term
- Coulombic term
Correct Answer: Coulombic term
Q5. In homology (comparative) modeling, the quality of the model depends most on:
- The number of small molecules docked
- The sequence identity between target and template proteins
- The volume of solvent used in simulation
- The number of hydrogen bond donors in the ligand
Correct Answer: The sequence identity between target and template proteins
Q6. Which scoring approach attempts to estimate binding free energy by combining molecular mechanics with continuum solvation calculations?
- Force-field minimization
- MM-PBSA/MM-GBSA
- 2D fingerprint similarity
- Rule-of-five filtering
Correct Answer: MM-PBSA/MM-GBSA
Q7. What does RMSD (root-mean-square deviation) commonly measure in docking or MD analyses?
- Change in pKa values
- Difference in atomic positions between two conformations
- Number of hydrogen bonds formed
- Molecular weight fluctuation
Correct Answer: Difference in atomic positions between two conformations
Q8. Which method is ligand-based and does not require a target 3D structure?
- Structure-based docking
- Pharmacophore modeling from known ligands
- Homology modeling of the receptor
- Molecular dynamics of the target
Correct Answer: Pharmacophore modeling from known ligands
Q9. Which factor is critical to model correctly because it can change ligand binding modes and interactions?
- Protonation states and tautomers of ligand and residues
- The color scheme of the visualization software
- Number of rotatable bonds in the protein backbone only
- The supplier of chemical reagents
Correct Answer: Protonation states and tautomers of ligand and residues
Q10. Virtual screening aims to:
- Experimentally measure binding constants for thousands of compounds
- Prioritize compounds from large libraries for experimental testing using computational filters
- Replace all in vitro assays permanently
- Predict clinical trial outcomes directly
Correct Answer: Prioritize compounds from large libraries for experimental testing using computational filters
Q11. Which descriptor type is commonly used in 3D-QSAR methods like CoMFA?
- Topological polar surface area only
- 3D steric and electrostatic fields mapped around aligned molecules
- Only 1D molecular formulas
- Protein sequence alignment scores
Correct Answer: 3D steric and electrostatic fields mapped around aligned molecules
Q12. Which of the following describes a pharmacophore?
- A set of steric and electronic features necessary for optimal interactions with a specific biological target
- The primary amino acid sequence of a protein
- A synthetic route to prepare a drug candidate
- A clinical endpoint used in trials
Correct Answer: A set of steric and electronic features necessary for optimal interactions with a specific biological target
Q13. What is the main limitation of rigid receptor docking?
- It cannot compute molecular weight
- It ignores protein flexibility and induced fit effects
- It always predicts exact binding affinities
- It requires quantum mechanical calculations for each ligand
Correct Answer: It ignores protein flexibility and induced fit effects
Q14. Which sampling method explores conformational space by random changes and acceptance criteria rather than deterministic integration of motion?
- Molecular dynamics with Verlet integrator
- Monte Carlo simulation
- Normal mode analysis
- Homology modeling refinement
Correct Answer: Monte Carlo simulation
Q15. In virtual screening validation, what does the ROC-AUC metric measure?
- Computational speed of docking
- Ability to distinguish actives from decoys across score thresholds
- Number of hydrogen bonds predicted by the docking software
- Protein folding energy
Correct Answer: Ability to distinguish actives from decoys across score thresholds
Q16. Which solvation model explicitly represents water molecules around the solute?
- Implicit solvent model (continuum)
- Explicit solvent model
- Vacuum calculations
- Gas-phase approximation
Correct Answer: Explicit solvent model
Q17. What is the purpose of energy minimization before MD simulations or docking refinement?
- To maximize the system temperature
- To relieve steric clashes and reduce strain to a nearby local minimum
- To change protein sequence
- To artificially increase binding affinity
Correct Answer: To relieve steric clashes and reduce strain to a nearby local minimum
Q18. Which practice helps account for receptor flexibility in docking studies?
- Ignoring water molecules completely
- Using ensemble docking with multiple receptor conformations
- Only docking to the apo crystal structure
- Restricting ligands to a single rotamer
Correct Answer: Using ensemble docking with multiple receptor conformations
Q19. Fragment-based drug design relies on:
- Screening very large, fully drug-like molecules only
- Identifying small, low-affinity fragments and growing or linking them to create higher-affinity leads
- Discarding structural information about the target
- Only QSAR without structural guidance
Correct Answer: Identifying small, low-affinity fragments and growing or linking them to create higher-affinity leads
Q20. Which of the following best explains ligand efficiency (LE)?
- Affinity normalized by molecular size, often ΔG per heavy atom
- Number of rotatable bonds in a ligand
- Total polar surface area only
- The solubility of a compound in water
Correct Answer: Affinity normalized by molecular size, often ΔG per heavy atom
Q21. CoMSIA differs from CoMFA primarily by:
- Using pharmacokinetics data instead of steric fields
- Including additional similarity fields like hydrophobic, H-bond donor/acceptor in a Gaussian-type manner
- Modeling protein folding pathways
- Requiring crystallographic data for all ligands
Correct Answer: Including additional similarity fields like hydrophobic, H-bond donor/acceptor in a Gaussian-type manner
Q22. Why is proper treatment of metal ions in active sites important in molecular modeling?
- Metal ions never affect ligand binding
- Incorrect metal parameterization can lead to wrong geometry and binding predictions
- Metals automatically improve scoring accuracy without special handling
- They only influence color rendering in visualization
Correct Answer: Incorrect metal parameterization can lead to wrong geometry and binding predictions
Q23. What is a common source of false positives in docking-based virtual screening?
- Over-reliance on accurate protonation states
- Scoring functions that inadequately model entropy, solvation, and receptor flexibility
- Using ensemble docking with many conformations
- Applying ADMET filters post-screening
Correct Answer: Scoring functions that inadequately model entropy, solvation, and receptor flexibility
Q24. QM/MM methods are used when:
- Only 1D descriptors are sufficient
- Electronic effects (e.g., reactions, charge transfer) in the active site must be modeled accurately while treating the rest classically
- Predicting solubility by simple rules
- Building homology models from low-identity templates only
Correct Answer: Electronic effects (e.g., reactions, charge transfer) in the active site must be modeled accurately while treating the rest classically
Q25. ADMET predictions in molecular modeling help primarily to:
- Forecast synthetic yield in the lab
- Estimate absorption, distribution, metabolism, excretion, and toxicity properties computationally
- Replace all safety testing
- Design clinical trial protocols
Correct Answer: Estimate absorption, distribution, metabolism, excretion, and toxicity properties computationally
Q26. In docking, what is the role of a grid map (grid-based scoring)?
- To store crystallographic B-factors only
- To precompute receptor properties (e.g., van der Waals, electrostatics) at points in space to speed scoring
- To visualize ligand synthetic routes
- To measure in vitro potency directly
Correct Answer: To precompute receptor properties (e.g., van der Waals, electrostatics) at points in space to speed scoring
Q27. Which validation technique assesses the early recognition capability of a virtual screening method?
- RMSD of a single pose
- Enrichment factor (EF) at top-ranked fraction
- Counting number of rotatable bonds
- Measuring computational runtime only
Correct Answer: Enrichment factor (EF) at top-ranked fraction
Q28. Which property is NOT directly evaluated by typical molecular mechanics force fields?
- Bonded interactions like bonds and angles
- Classical electrostatics and van der Waals interactions
- Electron delocalization and explicit bond breaking/forming
- Torsional potentials
Correct Answer: Electron delocalization and explicit bond breaking/forming
Q29. Why is generating multiple ligand conformers important before docking?
- To ensure rigid docking ignores ligand flexibility
- To represent possible bioactive shapes and improve chances of finding correct binding pose
- To reduce computational cost drastically by using only one shape
- To force ligand protonation changes automatically
Correct Answer: To represent possible bioactive shapes and improve chances of finding correct binding pose
Q30. Which practice improves reproducibility and reliability of computational drug design studies?
- Not reporting software versions and parameters
- Providing detailed methods: software, versions, parameters, training/test sets, and validation metrics
- Using only proprietary black-box methods without validation
- Publishing only positive results without negative controls
Correct Answer: Providing detailed methods: software, versions, parameters, training/test sets, and validation metrics
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.
Mail- Sachin@pharmacyfreak.com