GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1⃣
Reference
Ch. 1 — Natural Product Scaffolds → Lead Optimization
Stem
A pharmaceutical team identifies a potent alkaloid from a
medicinal plant that inhibits a CNS enzyme but has poor oral
bioavailability and high polar surface area. In preclinical ADME
studies the compound shows negligible brain penetration and
rapid hepatic first-pass metabolism. Which lead-optimization
,strategy most directly addresses oral absorption and brain
exposure while preserving the core scaffold?
Options
A. Introduce a permanently charged tertiary amine to increase
water solubility.
B. Mask polar groups as bioreversible esters (prodrug approach)
to improve permeability.
C. Add multiple polar hydroxyl groups to enhance hydrogen
bonding with plasma proteins.
D. Increase molecular weight by appending bulky aromatic rings
to reduce clearance.
Correct answer
B
Rationale — Correct (B)
Masking polar groups as bioreversible esters (a prodrug
strategy) transiently reduces polar surface area and increases
membrane permeability for oral absorption and CNS entry;
esterase-mediated conversion in plasma or target tissue
regenerates the active scaffold. This approach directly targets
permeability and first-pass issues while retaining the active
pharmacophore.
Rationale — Incorrect
A. Permanently charged amines improve aqueous solubility but
reduce passive BBB penetration and oral absorption.
C. Adding polar hydroxyls typically worsens membrane
permeability and may increase clearance via phase II
,conjugation.
D. Increasing molecular weight and lipophilicity with bulky rings
often raises metabolic liability and reduces brain penetration.
Teaching Point
Prodrugs can mask polarity to improve absorption and CNS
penetration, then regenerate active drug.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2️⃣
Reference
Ch. 1 — Structure-Based (Docking) vs Ligand-Based Design
Stem
An in-silico virtual screen using a single rigid crystal structure
returned many high-scoring ligands, but few validated in
biochemical assays. The target has a mobile binding-site loop
observed in fragment co-crystals. Which computational
refinement will most increase the chance that future virtual hits
translate into real binders?
Options
A. Rely exclusively on ligand-based pharmacophore models
derived from one known inhibitor.
B. Perform ensemble docking against multiple protein
conformations and rescoring with physics-based methods.
, C. Filter hits by predicted lipophilicity (logP) only, discarding
polar compounds.
D. Increase the virtual library size tenfold without changing
docking parameters.
Correct answer
B
Rationale — Correct (B)
Ensemble docking incorporates protein flexibility by using
multiple conformations (including loop movements) and
rescoring with physics-based energy estimates reduces false
positives from rigid docking assumptions, thereby improving hit
validation rates.
Rationale — Incorrect
A. Ligand-based models from a single inhibitor can miss
chemotypes that exploit alternate conformations.
C. Filtering only by logP ignores shape complementarity and key
interactions; may discard true binders.
D. Increasing library size without addressing the flawed docking
model will amplify false positives.
Teaching Point
Account for protein flexibility (ensemble docking) and physics-
based rescoring to reduce false positives.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1⃣
Reference
Ch. 1 — Natural Product Scaffolds → Lead Optimization
Stem
A pharmaceutical team identifies a potent alkaloid from a
medicinal plant that inhibits a CNS enzyme but has poor oral
bioavailability and high polar surface area. In preclinical ADME
studies the compound shows negligible brain penetration and
rapid hepatic first-pass metabolism. Which lead-optimization
,strategy most directly addresses oral absorption and brain
exposure while preserving the core scaffold?
Options
A. Introduce a permanently charged tertiary amine to increase
water solubility.
B. Mask polar groups as bioreversible esters (prodrug approach)
to improve permeability.
C. Add multiple polar hydroxyl groups to enhance hydrogen
bonding with plasma proteins.
D. Increase molecular weight by appending bulky aromatic rings
to reduce clearance.
Correct answer
B
Rationale — Correct (B)
Masking polar groups as bioreversible esters (a prodrug
strategy) transiently reduces polar surface area and increases
membrane permeability for oral absorption and CNS entry;
esterase-mediated conversion in plasma or target tissue
regenerates the active scaffold. This approach directly targets
permeability and first-pass issues while retaining the active
pharmacophore.
Rationale — Incorrect
A. Permanently charged amines improve aqueous solubility but
reduce passive BBB penetration and oral absorption.
C. Adding polar hydroxyls typically worsens membrane
permeability and may increase clearance via phase II
,conjugation.
D. Increasing molecular weight and lipophilicity with bulky rings
often raises metabolic liability and reduces brain penetration.
Teaching Point
Prodrugs can mask polarity to improve absorption and CNS
penetration, then regenerate active drug.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2️⃣
Reference
Ch. 1 — Structure-Based (Docking) vs Ligand-Based Design
Stem
An in-silico virtual screen using a single rigid crystal structure
returned many high-scoring ligands, but few validated in
biochemical assays. The target has a mobile binding-site loop
observed in fragment co-crystals. Which computational
refinement will most increase the chance that future virtual hits
translate into real binders?
Options
A. Rely exclusively on ligand-based pharmacophore models
derived from one known inhibitor.
B. Perform ensemble docking against multiple protein
conformations and rescoring with physics-based methods.
, C. Filter hits by predicted lipophilicity (logP) only, discarding
polar compounds.
D. Increase the virtual library size tenfold without changing
docking parameters.
Correct answer
B
Rationale — Correct (B)
Ensemble docking incorporates protein flexibility by using
multiple conformations (including loop movements) and
rescoring with physics-based energy estimates reduces false
positives from rigid docking assumptions, thereby improving hit
validation rates.
Rationale — Incorrect
A. Ligand-based models from a single inhibitor can miss
chemotypes that exploit alternate conformations.
C. Filtering only by logP ignores shape complementarity and key
interactions; may discard true binders.
D. Increasing library size without addressing the flawed docking
model will amplify false positives.
Teaching Point
Account for protein flexibility (ensemble docking) and physics-
based rescoring to reduce false positives.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
