Development of non-peptide peptidomimetics MCQs With Answer

Development of non-peptide peptidomimetics MCQs With Answer

This quiz collection introduces M.Pharm students to the design, development and formulation considerations of non-peptide peptidomimetics — small-molecule scaffolds that mimic peptide bioactivity without peptide bonds. It covers design strategies (bioisosteres, fragment-based design), scaffold types (peptoids, terphenyls, heterocycles), analytical and biophysical tools (SPR, NMR, X‑ray), ADME/PK challenges, and formulation approaches to improve solubility, stability and delivery. Questions emphasize mechanistic reasoning, examples of marketed peptidomimetics, and practical formulation solutions, providing a focused study aid to strengthen competence in translating peptide biology into drug-like non-peptidic molecules.

Q1. What is the principal aim when designing non-peptide peptidomimetics?

• Mimic the bioactive conformation and function of peptides using non-peptidic scaffolds to improve stability and pharmacokinetics
• Produce exact amino acid replicas to maintain enzymatic cleavage sites
• Create large polymeric carriers for peptide delivery
• Design molecules that only bind to enzymes degrading peptides

Correct Answer: Mimic the bioactive conformation and function of peptides using non-peptidic scaffolds to improve stability and pharmacokinetics

Q2. Which of the following pairs are classic examples of non-peptide peptidomimetic drugs?

• Captopril and Losartan
• Lisinopril and Vasopressin
• Penicillin and Streptomycin

Correct Answer: Captopril and Losartan

Q3. Which medicinal chemistry strategy is most commonly used to replace peptide amide bonds while retaining function?

• Bioisosteric replacement of amide bonds with heterocycles or isosteres
• Random polymerization of amino acids
• Increasing peptide chain length indefinitely
• Attachment of high molecular weight PEG chains only

Correct Answer: Bioisosteric replacement of amide bonds with heterocycles or isosteres

Q4. What structural class is described as N‑substituted glycine oligomers used as non-peptidic mimics of peptides?

• Peptoids
• Peptides
• Oligosaccharides
• Polypeptoids

Correct Answer: Peptoids

Q5. Which scaffold has been widely used as a non‑peptidic alpha‑helix mimetic to present side‑chain vectors at i, i+3/i+4 positions?

• Terphenyl-based scaffolds that present side-chain mimics at helix positions
• Polyglycine chains with free termini
• Linear polyethylene glycols
• Unmodified oligopeptides

Correct Answer: Terphenyl-based scaffolds that present side-chain mimics at helix positions

Q6. Compared with native peptides, a primary pharmacokinetic advantage of non‑peptide peptidomimetics is:

• Improved oral bioavailability and enhanced metabolic stability
• Higher susceptibility to proteolytic cleavage
• Absolute inability to cross membranes
• Guaranteed zero plasma protein binding

Correct Answer: Improved oral bioavailability and enhanced metabolic stability

Q7. Which biophysical method is the most suitable for real‑time measurement of binding kinetics (kon/koff) between a peptidomimetic and its receptor?

• Surface plasmon resonance (SPR)
• UV–Vis spectrophotometry
• Gel electrophoresis
• Circular dichroism for primary sequence

Correct Answer: Surface plasmon resonance (SPR)

Q8. How does macrocyclization or scaffold rigidification typically benefit peptidomimetic molecules?

• Reduces conformational entropy, increases target affinity and improves proteolytic stability
• Always increases molecular flexibility and decreases selectivity
• Makes molecules hydrophilic and decreases cell permeability
• Removes all chiral centers and abolishes activity

Correct Answer: Reduces conformational entropy, increases target affinity and improves proteolytic stability

Q9. Which modification most directly reduces susceptibility of a peptide backbone to protease cleavage in peptidomimetic design?

• Replacing amide bonds with non‑amide isosteres such as reduced amides, thioamides or heterocycles
• Adding multiple free amino termini to the backbone
• Increasing the number of canonical peptide bonds
• Removing all side-chains while keeping amide bonds

Correct Answer: Replacing amide bonds with non‑amide isosteres such as reduced amides, thioamides or heterocycles

Q10. Why is Lipinski’s rule of five often referenced during development of non‑peptide peptidomimetics?

• To guide optimization toward drug‑like properties predictive of oral absorption
• To ensure molecules are always peptides
• To mandate the use of 5 chiral centers in design
• To prevent any heteroatoms in the scaffold

Correct Answer: To guide optimization toward drug‑like properties predictive of oral absorption

Q11. Which formulation approach is commonly used to enhance aqueous solubility of lipophilic non‑peptide peptidomimetics?

• Cyclodextrin inclusion complexes to improve apparent solubility
• Complete removal of all excipients to avoid interactions
• Freezing the compound in solid form without excipients
• Formulating only as dry powders without carriers

Correct Answer: Cyclodextrin inclusion complexes to improve apparent solubility

Q12. Which structural technique provides information on three‑dimensional conformation of a peptidomimetic in solution?

• NMR spectroscopy (e.g., NOESY, ROESY) for solution conformational analysis
• Optical rotation for tertiary structure
• Mass spectrometry for high-resolution 3D geometry
• Thin layer chromatography for conformational mapping

Correct Answer: NMR spectroscopy (e.g., NOESY, ROESY) for solution conformational analysis

Q13. A key biochemical advantage of peptoids over comparable peptides is:

• Marked resistance to proteolytic degradation due to N‑substitution of the backbone
• Mandatory cleavage by all proteases
• Unfavorable synthesis compared with peptides
• Complete lack of secondary structure potential

Correct Answer: Marked resistance to proteolytic degradation due to N‑substitution of the backbone

Q14. What is the core principle of fragment‑based drug design applied to peptidomimetics?

• Identify low‑molecular‑weight fragments that bind weakly, then grow or link them to make high‑affinity ligands
• Use only full‑length peptides and trim them randomly
• Combine entire proteins as fragments to form larger complexes
• Rely exclusively on natural product libraries without optimization

Correct Answer: Identify low‑molecular‑weight fragments that bind weakly, then grow or link them to make high‑affinity ligands

Q15. Which property is least characteristic of a well‑designed non‑peptide peptidomimetic intended for oral use?

• Very high molecular weight exceeding 1000 Da
• Balanced lipophilicity for permeability
• Reduced number of hydrogen‑bond donors
• Metabolic stability against proteases and hepatic enzymes

Correct Answer: Very high molecular weight exceeding 1000 Da

Q16. Which heterocyclic motif is frequently used as a peptide bond surrogate introduced via click chemistry to rigidify backbones?

• 1,2,3‑Triazole linkages
• Furanose rings
• Sugar phosphates
• Long alkyl spacers without heteroatoms

Correct Answer: 1,2,3‑Triazole linkages

Q17. To improve cell permeability of a non‑peptide peptidomimetic targeting intracellular protein–protein interactions, a medicinal chemist would most likely:

• Reduce the number of hydrogen‑bond donors (e.g., N‑methylation) and mask polar groups
• Increase net polar surface area and add multiple charged groups
• Attach large polar PEG chains to the core scaffold
• Ensure the molecule is fully ionized at physiological pH

Correct Answer: Reduce the number of hydrogen‑bond donors (e.g., N‑methylation) and mask polar groups

Q18. In SAR (structure–activity relationship) studies of peptidomimetics, the goal is to:

• Systematically correlate chemical modifications with changes in biological activity to guide optimization
• Avoid any modifications to the lead molecule
• Synthesize random analogs without measuring activity
• Rely solely on theoretical predictions without experiments

Correct Answer: Systematically correlate chemical modifications with changes in biological activity to guide optimization

Q19. Which analytical technique is most routinely used for purity assessment and quantitation of synthetic non‑peptide peptidomimetics during development?

• High‑performance liquid chromatography (HPLC)
• Paper chromatography for quantitation
• Simple pH paper strips
• Visual color comparison

Correct Answer: High‑performance liquid chromatography (HPLC)

Q20. Which excipient is commonly used in parenteral formulations to reduce aggregation and improve solubility of hydrophobic small‑molecule peptidomimetics?

• Polysorbate 80 (surfactant)
• Sucrose crystals only
• Pure sodium chloride without any surfactant
• Unbuffered water with no additives

Correct Answer: Polysorbate 80 (surfactant)

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