GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A 68-year-old patient with chronic pain prefers “natural”
remedies and starts a concentrated extract from a plant used
traditionally for analgesia. A newly discovered alkaloid from
that plant binds the same neuronal sodium channel targeted by
,a marketed small molecule, but in preclinical assays the alkaloid
shows poor oral bioavailability and high first-pass metabolism.
Which lead-optimization strategy most directly addresses the
oral bioavailability problem while preserving target potency?
A. Increase molecular weight and polar surface area to reduce
clearance.
B. Design a prodrug that masks polar functional groups and is
converted systemically to the active alkaloid.
C. Introduce irreversible covalent warheads to increase duration
of action.
D. Remove stereocenters to simplify synthesis and increase
passive permeability.
Correct answer
B
Rationale — Correct (B)
Designing a prodrug that temporarily masks polar groups can
improve membrane permeability and reduce first-pass
metabolism, enabling higher oral systemic exposure while
relying on in vivo bioconversion to regenerate the active
alkaloid. Prodrug strategies are commonly used when potency
is preserved but ADME properties limit oral availability.
Rationale — Incorrect
A: Increasing molecular weight/polar surface area will usually
decrease permeability and worsen bioavailability.
C: Irreversible covalent modification may increase duration but
doesn’t directly fix absorption or first-pass loss and raises safety
,risks.
D: Removing stereocenters may change potency and selectivity
unpredictably; it doesn’t reliably increase permeability and risks
loss of activity.
Teaching point
Prodrugs can rescue potent but poorly bioavailable natural
leads.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A biotech company used high-throughput screening (HTS) to
find inhibitors of a kinase implicated in fibrosis. Hit compounds
demonstrate weak but reproducible inhibition in enzymatic
assays. In cellular assays many hits fail to produce the expected
antifibrotic phenotype despite good enzyme inhibition. Which
explanation best reflects a translational gap highlighted in
discovery?
A. HTS identifies only covalent inhibitors, which cannot function
in cells.
, B. Enzymatic potency does not guarantee cell permeability or
target engagement in the cellular context.
C. Enzyme assays are inherently inaccurate and should be
ignored.
D. Cellular phenotypes are unrelated to target modulation;
phenotype screening is redundant.
Correct answer
B
Rationale — Correct (B)
HTS enzymatic assays measure biochemical potency, but
cellular activity requires permeability, metabolic stability, and
engagement of the kinase in its native environment; lack of cell
activity often reflects poor cell penetration, efflux, or protein
binding. Bridging biochemical hits to cellular efficacy requires
ADME and cell-based target-engagement assays.
Rationale — Incorrect
A: HTS can identify reversible and covalent inhibitors; it’s not
limited to covalent hits.
C: Enzyme assays are valuable for initial potency measurement;
they are not inherently inaccurate.
D: Cellular phenotypes are often directly downstream of target
modulation; phenotype screening complements target-based
assays, not redundant.
Teaching point
Biochemical hits must be evaluated for cell permeability and
target engagement.
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A 68-year-old patient with chronic pain prefers “natural”
remedies and starts a concentrated extract from a plant used
traditionally for analgesia. A newly discovered alkaloid from
that plant binds the same neuronal sodium channel targeted by
,a marketed small molecule, but in preclinical assays the alkaloid
shows poor oral bioavailability and high first-pass metabolism.
Which lead-optimization strategy most directly addresses the
oral bioavailability problem while preserving target potency?
A. Increase molecular weight and polar surface area to reduce
clearance.
B. Design a prodrug that masks polar functional groups and is
converted systemically to the active alkaloid.
C. Introduce irreversible covalent warheads to increase duration
of action.
D. Remove stereocenters to simplify synthesis and increase
passive permeability.
Correct answer
B
Rationale — Correct (B)
Designing a prodrug that temporarily masks polar groups can
improve membrane permeability and reduce first-pass
metabolism, enabling higher oral systemic exposure while
relying on in vivo bioconversion to regenerate the active
alkaloid. Prodrug strategies are commonly used when potency
is preserved but ADME properties limit oral availability.
Rationale — Incorrect
A: Increasing molecular weight/polar surface area will usually
decrease permeability and worsen bioavailability.
C: Irreversible covalent modification may increase duration but
doesn’t directly fix absorption or first-pass loss and raises safety
,risks.
D: Removing stereocenters may change potency and selectivity
unpredictably; it doesn’t reliably increase permeability and risks
loss of activity.
Teaching point
Prodrugs can rescue potent but poorly bioavailable natural
leads.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A biotech company used high-throughput screening (HTS) to
find inhibitors of a kinase implicated in fibrosis. Hit compounds
demonstrate weak but reproducible inhibition in enzymatic
assays. In cellular assays many hits fail to produce the expected
antifibrotic phenotype despite good enzyme inhibition. Which
explanation best reflects a translational gap highlighted in
discovery?
A. HTS identifies only covalent inhibitors, which cannot function
in cells.
, B. Enzymatic potency does not guarantee cell permeability or
target engagement in the cellular context.
C. Enzyme assays are inherently inaccurate and should be
ignored.
D. Cellular phenotypes are unrelated to target modulation;
phenotype screening is redundant.
Correct answer
B
Rationale — Correct (B)
HTS enzymatic assays measure biochemical potency, but
cellular activity requires permeability, metabolic stability, and
engagement of the kinase in its native environment; lack of cell
activity often reflects poor cell penetration, efflux, or protein
binding. Bridging biochemical hits to cellular efficacy requires
ADME and cell-based target-engagement assays.
Rationale — Incorrect
A: HTS can identify reversible and covalent inhibitors; it’s not
limited to covalent hits.
C: Enzyme assays are valuable for initial potency measurement;
they are not inherently inaccurate.
D: Cellular phenotypes are often directly downstream of target
modulation; phenotype screening complements target-based
assays, not redundant.
Teaching point
Biochemical hits must be evaluated for cell permeability and
target engagement.
