Lead discovery and ligand libraries MCQs With Answer

Lead discovery and ligand libraries MCQs With Answer

This blog provides M.Pharm students with a focused set of multiple-choice questions on lead discovery and ligand libraries, emphasizing computational and experimental approaches used in modern drug discovery. It covers concepts such as virtual screening, fragment-based design, combinatorial libraries, docking and scoring, ligand efficiency metrics, ADMET profiling, and common pitfalls like PAINS. The questions are designed to deepen understanding by linking theoretical concepts to practical decision-making in hit identification and hit-to-lead progression. Each question includes concise answer choices and the correct answer to facilitate efficient revision and exam preparation for advanced pharmacy students.

Q1. What is the primary objective of lead discovery in drug development?

• To perform toxicology studies on marketed drugs
• To identify chemical starting points (hits) for optimization
• To scale up manufacturing processes
• To conduct Phase III clinical trials

Correct Answer: To identify chemical starting points (hits) for optimization

Q2. Which two major approaches are used in virtual screening for lead discovery?

• In vitro and in vivo screening
• Ligand-based and structure-based virtual screening
• Fragment-based and phenotypic screening
• ADMET profiling and medicinal chemistry

Correct Answer: Ligand-based and structure-based virtual screening

Q3. What best describes fragment-based lead discovery (FBLD)?

• Screening large drug-like molecules to find nanomolar hits
• Using high-throughput phenotypic assays to find leads
• Using small, low-molecular-weight fragments that bind weakly and are grown or linked
• Applying combinatorial libraries to generate macrocycles only

Correct Answer: Using small, low-molecular-weight fragments that bind weakly and are grown or linked

Q4. How is a “hit” differentiated from a “lead” in early drug discovery?

• A hit is always more potent than a lead
• Hits are initial actives; leads are optimized with improved potency and ADME
• Leads are untested computational predictions, hits are approved drugs
• Hits must be covalent inhibitors; leads are non-covalent

Correct Answer: Hits are initial actives; leads are optimized with improved potency and ADME

Q5. What is the main goal of diversity-oriented synthesis (DOS) when creating ligand libraries?

• To produce only stereochemically pure single-target series
• To create structurally diverse compounds that explore wide chemical space
• To focus exclusively on lipid-soluble molecules
• To synthesize only analogs of a known drug

Correct Answer: To create structurally diverse compounds that explore wide chemical space

Q6. Which set correctly summarizes Lipinski’s “Rule of Five” typical thresholds?

• More than 5 H-bond donors, more than 10 H-bond acceptors, MW > 800, logP > 10
• 5 or fewer H-bond donors, 10 or fewer H-bond acceptors, MW < 500, logP < 5
• Zero rotatable bonds, polar surface area < 20 Ų, MW < 200
• At least one charged center, MW > 600, logP < -1

Correct Answer: 5 or fewer H-bond donors, 10 or fewer H-bond acceptors, MW < 500, logP < 5

Q7. What is the purpose of applying PAINS filters to screening libraries?

• To enrich libraries with metal chelators only
• To identify compounds that are likely pan-assay interference substances and remove them
• To select for molecules that cross the blood–brain barrier
• To prioritize covalent modifiers exclusively

Correct Answer: To identify compounds that are likely pan-assay interference substances and remove them

Q8. Which types of scoring functions are commonly used in molecular docking?

• Empirical, force-field, and knowledge-based scoring functions
• Clinical outcome-based and genomic scoring functions
• Hydrophobicity-only and PSA-only scoring functions
• Enzymatic turnover rate and metabolic clearance scoring functions

Correct Answer: Empirical, force-field, and knowledge-based scoring functions

Q9. What does ligand efficiency (LE) measure in lead optimization?

• The ratio of aqueous solubility to molecular weight
• Binding energy per non-hydrogen (heavy) atom
• Fraction unbound in plasma
• The number of rotatable bonds per ring

Correct Answer: Binding energy per non-hydrogen (heavy) atom

Q10. How is lipophilic ligand efficiency (LLE) commonly calculated?

• logP minus pIC50
• pIC50 minus logP
• pKa times molecular weight
• pIC50 divided by polar surface area

Correct Answer: pIC50 minus logP

Q11. Which is a common limitation of high-throughput screening (HTS) libraries?

• They always guarantee clinical success
• High cost and higher false positive rate due to assay artifacts
• They cannot be used with automation
• HTS libraries contain only covalent binders

Correct Answer: High cost and higher false positive rate due to assay artifacts

Q12. What defines a combinatorial chemical library?

• A systematic set of compounds generated by combining sets of building blocks in parallel synthesis
• A single, highly optimized lead compound
• Only natural product extracts pooled from different sources
• Microbial fermentation broths screened without fractionation

Correct Answer: A systematic set of compounds generated by combining sets of building blocks in parallel synthesis

Q13. What is “scaffold hopping” in medicinal chemistry?

• Increasing molecular weight by adding long alkyl chains
• Changing the core (scaffold) of a molecule to find new chemotypes preserving activity
• Replacing all heteroatoms with carbon
• Only performing prodrug conversions

Correct Answer: Changing the core (scaffold) of a molecule to find new chemotypes preserving activity

Q14. How do covalent inhibitors typically achieve prolonged target inhibition?

• By forming reversible hydrogen bonds exclusively
• By forming a covalent bond with a nucleophilic residue in the target protein
• By increasing metabolic clearance rapidly
• By binding to the cell membrane non-specifically

Correct Answer: By forming a covalent bond with a nucleophilic residue in the target protein

Q15. Why is early ADMET profiling important during hit-to-lead stage?

• To delay identification of liabilities until clinical trials
• To reduce later-stage attrition by identifying absorption, distribution, metabolism, excretion, and toxicity issues early
• To guarantee a compound will be approved by regulators
• To replace the need for potency optimization

Correct Answer: To reduce later-stage attrition by identifying absorption, distribution, metabolism, excretion, and toxicity issues early

Q16. What is the core concept of pharmacophore modeling in ligand discovery?

• Defining a 3D arrangement of essential steric and electronic features required for activity
• Predicting metabolic half-life from logP alone
• Designing only peptidic inhibitors
• Measuring protein tertiary structure by NMR noise reduction

Correct Answer: Defining a 3D arrangement of essential steric and electronic features required for activity

Q17. What does the area under the ROC curve (AUC) indicate when evaluating virtual screening performance?

• The physical size of the ligand library screened
• How well the method distinguishes actives from inactives (enrichment)
• The number of rotatable bonds in top hits
• Only the binding free energy in kcal/mol

Correct Answer: How well the method distinguishes actives from inactives (enrichment)

Q18. Why is ensemble docking used rather than single-structure docking?

• To increase computational speed by using fewer conformations
• To account for protein flexibility by docking to multiple receptor conformations
• To ensure only covalent interactions are modeled
• To ignore solvent effects completely

Correct Answer: To account for protein flexibility by docking to multiple receptor conformations

Q19. Which statement best reflects exceptions to Lipinski’s rules?

• No clinically used drug can ever violate Lipinski’s rules
• Some drugs, such as natural products and macrocycles, may violate Lipinski’s rules yet still be successful
• Lipinski’s rules mandate a compound must be charged
• Lipinski only applies to topical formulations

Correct Answer: Some drugs, such as natural products and macrocycles, may violate Lipinski’s rules yet still be successful

Q20. During hit-to-lead optimization which objectives are typically prioritized?

• Only increasing molecular weight without regard to ADME
• Improving potency, selectivity, ADME properties, and synthetic tractability
• Eliminating all polar functionality regardless of activity
• Converting leads to irreversible covalent probes only

Correct Answer: Improving potency, selectivity, ADME properties, and synthetic tractability

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