MChem Master of Chemistry Master of Chemistry: Pharmaceutical Chemistry 4 ā Questions and Answers
Question 1: Which strategy is used to overcome rapid metabolism of a drug by deuterium incorporation?
- Deuterium isotope effect slows CāH bond cleavage at metabolic sites (Correct answer)
- Deuterium increases logP to reduce hepatic extraction
- Deuterium blocks CYP3A4 active site sterically
- Deuterium forms stronger hydrogen bonds with plasma proteins
Correct answer: Deuterium isotope effect slows CāH bond cleavage at metabolic sites
Replacing metabolically vulnerable CāH bonds with CāD bonds exploits the primary kinetic isotope effect, slowing oxidative metabolism at those sites.
Question 2: What is the primary goal of bioisosteric replacement in drug optimization?
- Increase molecular weight to improve receptor binding
- Maintain biological activity while modifying physicochemical properties (Correct answer)
- Add reactive functional groups for covalent binding
- Reduce synthetic complexity by removing stereocenters
Correct answer: Maintain biological activity while modifying physicochemical properties
Bioisosteric replacement substitutes one functional group with a similarly shaped/polar group to retain target affinity while improving ADMET properties or patentability.
Question 3: Which ICH guideline specifically addresses impurity thresholds and qualification requirements for drug substances?
- ICH Q1A
- ICH Q3A (Correct answer)
- ICH Q6A
- ICH Q8
Correct answer: ICH Q3A
ICH Q3A (Impurities in New Drug Substances) defines reporting, identification, and qualification thresholds for chemical impurities in APIs.
Question 4: In fragment-based drug discovery (FBDD), what molecular weight range typically defines a fragment?
- 50ā100 Da
- 100ā250 Da (Correct answer)
- 300ā500 Da
- 500ā700 Da
Correct answer: 100ā250 Da
Fragments are typically 100ā250 Da (rule of three: MW ā¤300, H-bond donors ā¤3, cLogP ā¤3), allowing efficient exploration of chemical space with weak but ligand-efficient binders.
Question 5: Which mechanism of resistance to Ī²-lactam antibiotics is most clinically significant?
- Decreased outer membrane permeability
- Production of Ī²-lactamase enzymes (Correct answer)
- Overexpression of efflux pumps
- Mutation of the 30S ribosomal subunit
Correct answer: Production of Ī²-lactamase enzymes
Ī²-Lactamase production is the predominant resistance mechanism; these enzymes hydrolyze the Ī²-lactam ring, rendering the antibiotic inactive.
Question 6: The Cmax/MIC ratio is the key pharmacokinetic/pharmacodynamic (PK/PD) index for which class of antibiotics?
- Ī²-Lactams
- Aminoglycosides (Correct answer)
- Carbapenems
- Macrolides
Correct answer: Aminoglycosides
Aminoglycosides exhibit concentration-dependent killing, making their Cmax/MIC ratio the primary PK/PD index predicting efficacy.
Question 7: Which computational method is most appropriate for predicting the binding pose of a small molecule in a known protein crystal structure?
- Quantitative structure-activity relationship (QSAR)
- Molecular docking (Correct answer)
- Homology modeling
- Molecular dynamics (MD) simulation
Correct answer: Molecular docking
Molecular docking algorithms score and rank binding poses of small molecules within a defined protein binding site derived from crystallographic data.
MChem Master of Chemistry Master of Chemistry: Pharmaceutical Chemistry 4
Which strategy is used to overcome rapid metabolism of a drug by deuterium incorporation?