Rational drug design using peptidomimetics MCQs With Answer

Introduction: Rational drug design using peptidomimetics explores how modified peptides and peptide-like molecules are engineered to combine the specificity of peptides with improved pharmacokinetic and pharmacodynamic properties. For M.Pharm students, understanding peptidomimetics requires integrating protein structure, medicinal chemistry, and formulation strategies to enhance stability, membrane permeability, receptor affinity and oral bioavailability. This blog-style MCQ set targets core concepts such as backbone and side-chain modifications, cyclic and stapled peptides, β- and γ-peptides, retro-inverso and peptoid strategies, computational design approaches, and ADME/immunogenicity considerations. These questions are intended to deepen conceptual knowledge and support practical thinking in designing peptidomimetic therapeutics.

Q1. What is the primary rationale for converting a bioactive peptide into a peptidomimetic?

• To increase the molecular weight for better receptor binding
• To improve metabolic stability, permeability and selectivity while retaining target recognition
• To make the peptide more hydrophilic and increase renal clearance
• To reduce the affinity for the biological target

Correct Answer: To improve metabolic stability, permeability and selectivity while retaining target recognition

Q2. Which modification is most commonly used to increase protease resistance of peptide drugs?

• Introduction of polar PEG chains into the backbone
• Substitution of L-amino acids with D-amino acids or N-methylation of amide bonds
• Reducing molecular rigidity by converting cyclic peptides to linear forms
• Adding multiple free carboxylic acid termini

Correct Answer: Substitution of L-amino acids with D-amino acids or N-methylation of amide bonds

Q3. Which class of peptidomimetics uses the peptide side-chain sequence but replaces the peptide backbone with N-substituted glycines?

• β-peptides
• Peptoids
• Retro-inverso peptides
• Stapled peptides

Correct Answer: Peptoids

Q4. Retro-inverso peptides are designed by which principle?

• Reversing the amino acid sequence and replacing L-residues by D-residues to preserve side-chain topology
• Cyclizing the N- and C-termini to form a head-to-tail macrocycle
• Replacing backbone amide bonds with ester linkages to increase flexibility
• Adding bulky aromatic groups to side chains to increase lipophilicity

Correct Answer: Reversing the amino acid sequence and replacing L-residues by D-residues to preserve side-chain topology

Q5. Which structural mimic is most commonly used to stabilize an alpha-helical conformation in peptidomimetics for inhibiting protein–protein interactions?

• Beta-turn mimetics composed solely of glycine residues
• Stapled peptides that introduce a hydrocarbon bridge between i and i+4 residues
• Peptoids with alternating polar and nonpolar residues
• Linear peptides with multiple proline residues

Correct Answer: Stapled peptides that introduce a hydrocarbon bridge between i and i+4 residues

Q6. Which backbone modification creates oligomers with enhanced resistance to proteolysis and the ability to form stable secondary structures distinct from α-peptides?

• Conversion to retropeptides
• Use of β-amino acids to form β-peptides
• Attachment of long PEG chains to the N-terminus
• Introducing glycosylation at side chains

Correct Answer: Use of β-amino acids to form β-peptides

Q7. In rational design of peptidomimetics, which computational approach is most useful for predicting peptide–protein interface hot spots for mimicry?

• Quantitative structure–toxicity relationship (QSTR) modeling
• Molecular docking and molecular dynamics simulations focusing on interface residues
• Simple logP prediction to estimate hydrophobicity
• Principal component analysis of chromatographic retention times

Correct Answer: Molecular docking and molecular dynamics simulations focusing on interface residues

Q8. Which modification is specifically intended to improve oral bioavailability of peptidomimetics by enhancing membrane permeability?

• Increasing net negative charge
• Incorporation of lipidic side-chains, N-methylation, and cyclization to reduce polar surface area
• Removal of side-chain aromatic groups
• Extensive glycosylation to increase size

Correct Answer: Incorporation of lipidic side-chains, N-methylation, and cyclization to reduce polar surface area

Q9. Which of the following is an example of a non-peptidic α-helix mimetic used in disrupting protein–protein interactions?

• Terphenyl scaffolds that spatially project side-chain mimics at i, i+3, i+7 positions
• Poly-L-lysine homopolymers
• Random-coil peptoids lacking defined side-chain orientation
• Glycine-rich heptapeptides

Correct Answer: Terphenyl scaffolds that spatially project side-chain mimics at i, i+3, i+7 positions

Q10. Which synthetic technique is central to systematic construction and screening of peptidomimetic libraries?

• Solution-phase enzymatic ligation exclusively
• Solid-phase synthesis combined with combinatorial split-and-pool methods
• Simple one-pot fermentation of peptide analogues
• Direct extraction from natural sources without modification

Correct Answer: Solid-phase synthesis combined with combinatorial split-and-pool methods

Q11. Why is N-methylation of backbone amides used in peptidomimetic design?

• To increase backbone hydrogen bonding capacity and increase flexibility
• To block backbone hydrogen bonding, reduce conformational freedom, and improve membrane permeability
• To introduce a reactive electrophile for covalent binding
• To enhance susceptibility to proteases

Correct Answer: To block backbone hydrogen bonding, reduce conformational freedom, and improve membrane permeability

Q12. Which factor is LEAST likely to reduce immunogenicity of a therapeutic peptidomimetic?

• Use of D-amino acids and non-natural residues
• Conjugation to large immunogenic carrier proteins
• Cyclization and backbone modification to hide epitopes
• Reducing T-cell epitope sequences via sequence alteration

Correct Answer: Conjugation to large immunogenic carrier proteins

Q13. Stapled peptides commonly improve which combination of properties compared to the linear parent peptide?

• Reduced target affinity and increased renal clearance
• Increased α-helicity, improved cell permeability and protease resistance
• Higher entropic cost of binding and decreased specificity
• Complete elimination of off-target binding without structural change

Correct Answer: Increased α-helicity, improved cell permeability and protease resistance

Q14. Which peptidomimetic strategy best preserves side-chain topology while altering backbone orientation to resist proteolysis?

• Replacement of backbone amide with thioester linkages throughout
• Retro-inverso modification where sequence is reversed and L→D substitution is done
• Extensive PEGylation at every side chain
• Converting all residues to glycine

Correct Answer: Retro-inverso modification where sequence is reversed and L→D substitution is done

Q15. When designing peptidomimetics to inhibit proteases, which design element is most critical?

• Maximizing overall flexibility to adapt to active site dynamics
• Incorporation of a non-cleavable isostere at the scissile bond to prevent hydrolysis
• Increasing the peptide’s net positive charge only
• Replacing active-site interacting residues with glycine

Correct Answer: Incorporation of a non-cleavable isostere at the scissile bond to prevent hydrolysis

Q16. Which statement best describes a backbone isostere used in peptidomimetics?

• An atom or group that increases flexibility but changes side-chain positions
• An amide bond replacement (e.g., reduced amide, thioamide, olefin, or ketomethylene) that mimics geometry and H-bonding properties
• A bulky appendage added to side chains to block binding
• A carbohydrate moiety attached to the N-terminus

Correct Answer: An amide bond replacement (e.g., reduced amide, thioamide, olefin, or ketomethylene) that mimics geometry and H-bonding properties

Q17. In developing peptidomimetics, which ADME parameter is most directly improved by cyclization?

• Hepatic metabolism via induction of CYP enzymes
• Proteolytic stability and sometimes membrane permeability due to reduced conformational flexibility
• Rapid renal excretion due to increased polarity
• Increased antigen presentation through MHC binding

Correct Answer: Proteolytic stability and sometimes membrane permeability due to reduced conformational flexibility

Q18. A medicinal chemist aims to design a selective antagonist for a GPCR peptide-binding site. Which peptidomimetic design approach is most appropriate initially?

• Design of short, linear unmodified peptides containing multiple Lys residues
• Mapping of key receptor–ligand contact residues followed by constrained mimetics (cyclization, stapling, or non-peptidic scaffolds) to present the pharmacophore
• Random mutation of the peptide sequence without structural modeling
• Converting the peptide into a full-length protein to increase contact area

Correct Answer: Mapping of key receptor–ligand contact residues followed by constrained mimetics (cyclization, stapling, or non-peptidic scaffolds) to present the pharmacophore

Q19. Which analytical technique is most informative for verifying that a peptidomimetic has adopted the intended secondary structure (e.g., α-helix)?

• Size-exclusion chromatography alone
• Circular dichroism (CD) spectroscopy and corroboration by NMR or X-ray crystallography
• Thin-layer chromatography
• Elemental analysis only

Correct Answer: Circular dichroism (CD) spectroscopy and corroboration by NMR or X-ray crystallography

Q20. Which factor is a common limitation when transitioning peptide leads to clinically useful peptidomimetics?

• Peptidomimetics always have superior oral bioavailability with no trade-offs
• Balancing target affinity with improved ADME properties often requires compromises and iterative optimization
• Peptidomimetics cannot be synthesized by solid-phase methods
• There is no need to consider toxicity or immunogenicity once stability is improved

Correct Answer: Balancing target affinity with improved ADME properties often requires compromises and iterative optimization

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