CADD in peptidomimetics design MCQs With Answer

CADD in Peptidomimetics Design MCQs With Answer

This quiz collection focuses on computational approaches used to design peptidomimetics for M.Pharm students studying Proteins and Protein Formulations. It covers structure-based and ligand-based techniques such as molecular docking, molecular dynamics, pharmacophore modeling, QSAR, free energy methods, and ADME/T prediction tailored to peptide-like molecules. Questions emphasize challenges unique to peptidomimetics—conformational flexibility, backbone modifications, macrocyclization, proteolytic stability, and scoring limitations—while linking theory to practical workflows used in modern CADD pipelines. Use these MCQs for revision, classroom assessment, or exam practice to deepen conceptual and applied understanding of computational peptidomimetic design.

Q1. Which computational challenge is most characteristic of docking peptidomimetics compared to small rigid molecules?

• Insufficient atom typing libraries
• High conformational flexibility and larger rotatable bond count
• Inability to represent covalent bonds
• Lack of scoring functions for hydrogen bonds

Correct Answer: High conformational flexibility and larger rotatable bond count

Q2. In designing peptidomimetics, which backbone modification is commonly used to reduce proteolytic degradation while retaining side-chain display?

• Terminal acetylation only
• α-to-β amino acid substitution (β-peptides)
• Peptide amidation at central residues
• Adding polyethylene glycol (PEG) to side chains

Correct Answer: α-to-β amino acid substitution (β-peptides)

Q3. Which in silico method is most appropriate for identifying conserved spatial arrangements of pharmacophoric features from known peptide binders?

• Molecular dynamics (MD) simulation
• Pharmacophore modeling
• Homology modeling
• Quantum mechanics (QM) single point energy

Correct Answer: Pharmacophore modeling

Q4. For ranking binding affinities of peptidomimetic candidates after docking, which approach offers improved accuracy by incorporating solvation and entropic contributions?

• Rigid-body docking score only
• MM-GBSA/MM-PBSA rescoring
• Simple hydrogen bond count
• Torsional strain energy alone

Correct Answer: MM-GBSA/MM-PBSA rescoring

Q5. What is a primary advantage of designing macrocyclic peptidomimetics in CADD workflows?

• Easier synthesis than linear peptides
• Enhanced conformational restriction improving binding affinity and protease resistance
• Complete elimination of polar surface area
• Guaranteed oral bioavailability without further optimization

Correct Answer: Enhanced conformational restriction improving binding affinity and protease resistance

Q6. Which force field property is crucial when performing molecular dynamics of peptidomimetics to capture backbone conformational preferences accurately?

• Electrostatic cutoff distance only
• Accurate parameterization of backbone dihedral potentials and nonstandard residues
• Exclusion of van der Waals terms
• Use of exclusively implicit solvent models

Correct Answer: Accurate parameterization of backbone dihedral potentials and nonstandard residues

Q7. In virtual library design of peptidomimetics, what is scaffold hopping intended to achieve?

• Replace a peptide bond with a sugar moiety
• Change core scaffold to explore chemical diversity while preserving key interactions
• Optimize only ADME properties without structural changes
• Convert macrocycles into linear peptides

Correct Answer: Change core scaffold to explore chemical diversity while preserving key interactions

Q8. When integrating explicit water in peptide–protein docking, what role do structured water molecules often play?

• Always destabilize peptide binding
• Act as mediators of hydrogen-bond networks between ligand and protein
• Replace hydrophobic interactions by ionic bonds
• Prevent any conformational change in the binding site

Correct Answer: Act as mediators of hydrogen-bond networks between ligand and protein

Q9. Which in silico descriptor is particularly informative in QSAR models for peptidomimetics regarding membrane permeability?

• Topological polar surface area (tPSA)
• Molar refractivity only
• Number of aromatic rings exclusively
• Hydrogen bond count ignoring rotatable bonds

Correct Answer: Topological polar surface area (tPSA)

Q10. What is the purpose of using rotamer libraries in computational peptidomimetic design?

• To model solvent dielectric behavior
• To provide common side-chain conformations for sampling and reducing conformational search space
• To automatically predict ADMET properties
• To generate quantum mechanical parameters for nonstandard residues

Correct Answer: To provide common side-chain conformations for sampling and reducing conformational search space

Q11. Which free-energy method provides the most rigorous (but computationally expensive) estimate of relative binding free energies between two peptidomimetics?

• Docking score comparison
• Free Energy Perturbation (FEP) or Thermodynamic Integration (TI)
• Ligand efficiency metric
• Empirical scoring function reweighting

Correct Answer: Free Energy Perturbation (FEP) or Thermodynamic Integration (TI)

Q12. In homology modeling of protein targets for peptide docking, which region requires particular care due to direct interaction with peptidomimetics?

• Signal peptide only
• Binding site loops and flexible side chains
• Transmembrane helix distant from ligand
• Unstructured N-terminal tags used for purification

Correct Answer: Binding site loops and flexible side chains

Q13. Which strategy is commonly used in silico to reduce the entropic penalty of a peptide binding to a protein?

• Increase peptide length arbitrarily
• Introduce conformational constraints such as stapling or cyclization
• Replace polar residues with charged residues
• Remove all hydrophobic residues

Correct Answer: Introduce conformational constraints such as stapling or cyclization

Q14. When modeling noncanonical residues or peptidomimetic linkers, what step is essential before MD or docking simulations?

• Assume existing small-molecule parameters are sufficient
• Parameterize partial charges and force field parameters for the new moieties
• Always convert the system to implicit solvent
• Ignore torsional parameters to speed up simulations

Correct Answer: Parameterize partial charges and force field parameters for the new moieties

Q15. Which ADMET predictor is specifically important for peptidomimetics intended for oral delivery?

• Plasma protein binding only
• Permeability (Caco-2/PAMPA) and proteolytic stability
• Rate of color change in solution
• Boiling point prediction

Correct Answer: Permeability (Caco-2/PAMPA) and proteolytic stability

Q16. In peptide docking protocols, ensemble docking refers to which practice?

• Docking ligands to multiple protein conformations or multiple ligand conformations
• Docking only one rigid ligand into one rigid receptor
• Using only quantum mechanics for sampling
• Docking peptides exclusively into membrane proteins

Correct Answer: Docking ligands to multiple protein conformations or multiple ligand conformations

Q17. What is the benefit of using fragment-based design in peptidomimetics CADD?

• Allows rapid identification of small interaction motifs that can be linked or grown into higher-affinity mimetics
• Eliminates the need for any experimental validation
• Ensures the final molecule will be non-immunogenic
• Provides direct prediction of long-term toxicity

Correct Answer: Allows rapid identification of small interaction motifs that can be linked or grown into higher-affinity mimetics

Q18. Which scoring function component is usually NOT directly captured by standard rigid docking scores but is crucial for peptidomimetic binding?

• Lennard-Jones van der Waals interactions
• Conformational entropy loss upon binding
• Electrostatic complementarity
• Hydrogen-bond geometry

Correct Answer: Conformational entropy loss upon binding

Q19. In designing peptidomimetics to mimic an α-helix, which tactic is commonly used computationally to preserve side-chain presentation?

• Linearizing all residues
• Using helix-mimetic scaffolds or stapled peptides to fix i→i+4 side-chain orientation
• Removing all charged residues
• Substituting with polyalanine sequences only

Correct Answer: Using helix-mimetic scaffolds or stapled peptides to fix i→i+4 side-chain orientation

Q20. Which experimental data type, when integrated into CADD workflows, most improves the modeling of peptide–protein complexes?

• Circular dichroism data only for global folding
• High-resolution structural restraints (X-ray/cryo-EM/NMR) to guide docking and ensemble selection
• UV–Vis absorbance spectra
• Simple mass measurements without fragmentation

Correct Answer: High-resolution structural restraints (X-ray/cryo-EM/NMR) to guide docking and ensemble selection

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