GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
Q1
Reference
Ch. — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A 68-year-old patient with chronic kidney disease (eGFR 28
mL/min/1.73 m²) presents with a severe fungal infection. An
investigational antifungal was identified from a medicinal-plant
extract showing potent in-vitro enzyme inhibition but very low
,aqueous solubility and high protein binding. As a lead-
optimization chemist, which strategy best addresses the
translational risk of poor oral bioavailability while preserving
the plant-derived pharmacophore?
Options
A. Convert the active scaffold into a prodrug that increases
aqueous solubility and undergoes predictable enzymatic
conversion to the active moiety.
B. Add bulky lipophilic substituents to increase membrane
permeability and reduce protein binding.
C. Replace polar functional groups with methyl groups to
reduce polar surface area and improve passive absorption.
D. Rely on high protein binding because it typically increases
apparent half-life and reduces dosing frequency.
Correct answer
A
Rationales
Correct (A): Prodrug design is a standard medicinal-chemistry
strategy to transiently mask polar groups, increase solubility or
permeability, and then rely on enzymatic conversion (e.g.,
esterases) to release the active pharmacophore. It addresses
bioavailability while preserving the plant-derived active core,
important in renal impairment where predictable conversion
and avoidance of accumulation are critical.
Incorrect (B): Adding bulky lipophilic groups can increase
permeability but also aggravate high protein binding and reduce
,free drug available for effect; it may worsen distribution and
clearance issues in renal disease.
Incorrect (C): Replacing polar groups with methyls may reduce
aqueous solubility and can remove key H-bond interactions
essential for target binding—risking loss of activity.
Incorrect (D): High protein binding does not reliably improve
therapeutic index; only unbound concentration is
pharmacologically active and unpredictable in renal disease
where competing displaced binding and altered albumin levels
occur.
Teaching point
Prodrugs can improve solubility/permeability while preserving
pharmacophore function.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. Drug
Discovery: From Medicinal Plants to Computer-Aided Drug
Design.
Q2
Reference
Ch. — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A biotech company uses high-throughput screening (HTS)
, against an enzyme target expressed in bacteria. Several hits
show submicromolar inhibition in the enzyme assay but fail to
show cellular activity in mammalian pathogen-infected cells.
Which explanation most coherently integrates pharmacologic
and translational principles from lead selection?
Options
A. Hits likely inhibit a bacterial homolog in the HTS assay but are
cell-impermeant or are efflux substrates in mammalian cells.
B. Enzyme inhibition in vitro guarantees cellular activity; lack of
effect is due to wrong incubation time in cell assays.
C. The HTS hits are probably unstable in assay buffer; instability
explains loss of activity in cellular assays.
D. Cellular assays are prone to nonspecific toxicity; the loss of
activity implies general cytotoxicity masked in enzyme assays.
Correct answer
A
Rationales
Correct (A): HTS against isolated enzymes can give false
positives that lack cellular permeability or are substrates for
mammalian efflux transporters, preventing sufficient
intracellular concentration—key translation issue. Also species
homolog differences can affect relevance.
Incorrect (B): In vitro enzyme inhibition does not guarantee
cellular activity due to ADME/transport/permeability barriers;
incubation time alone is an insufficient blanket explanation.
Incorrect (C): Buffer instability can occur but would usually
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
Q1
Reference
Ch. — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A 68-year-old patient with chronic kidney disease (eGFR 28
mL/min/1.73 m²) presents with a severe fungal infection. An
investigational antifungal was identified from a medicinal-plant
extract showing potent in-vitro enzyme inhibition but very low
,aqueous solubility and high protein binding. As a lead-
optimization chemist, which strategy best addresses the
translational risk of poor oral bioavailability while preserving
the plant-derived pharmacophore?
Options
A. Convert the active scaffold into a prodrug that increases
aqueous solubility and undergoes predictable enzymatic
conversion to the active moiety.
B. Add bulky lipophilic substituents to increase membrane
permeability and reduce protein binding.
C. Replace polar functional groups with methyl groups to
reduce polar surface area and improve passive absorption.
D. Rely on high protein binding because it typically increases
apparent half-life and reduces dosing frequency.
Correct answer
A
Rationales
Correct (A): Prodrug design is a standard medicinal-chemistry
strategy to transiently mask polar groups, increase solubility or
permeability, and then rely on enzymatic conversion (e.g.,
esterases) to release the active pharmacophore. It addresses
bioavailability while preserving the plant-derived active core,
important in renal impairment where predictable conversion
and avoidance of accumulation are critical.
Incorrect (B): Adding bulky lipophilic groups can increase
permeability but also aggravate high protein binding and reduce
,free drug available for effect; it may worsen distribution and
clearance issues in renal disease.
Incorrect (C): Replacing polar groups with methyls may reduce
aqueous solubility and can remove key H-bond interactions
essential for target binding—risking loss of activity.
Incorrect (D): High protein binding does not reliably improve
therapeutic index; only unbound concentration is
pharmacologically active and unpredictable in renal disease
where competing displaced binding and altered albumin levels
occur.
Teaching point
Prodrugs can improve solubility/permeability while preserving
pharmacophore function.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. Drug
Discovery: From Medicinal Plants to Computer-Aided Drug
Design.
Q2
Reference
Ch. — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A biotech company uses high-throughput screening (HTS)
, against an enzyme target expressed in bacteria. Several hits
show submicromolar inhibition in the enzyme assay but fail to
show cellular activity in mammalian pathogen-infected cells.
Which explanation most coherently integrates pharmacologic
and translational principles from lead selection?
Options
A. Hits likely inhibit a bacterial homolog in the HTS assay but are
cell-impermeant or are efflux substrates in mammalian cells.
B. Enzyme inhibition in vitro guarantees cellular activity; lack of
effect is due to wrong incubation time in cell assays.
C. The HTS hits are probably unstable in assay buffer; instability
explains loss of activity in cellular assays.
D. Cellular assays are prone to nonspecific toxicity; the loss of
activity implies general cytotoxicity masked in enzyme assays.
Correct answer
A
Rationales
Correct (A): HTS against isolated enzymes can give false
positives that lack cellular permeability or are substrates for
mammalian efflux transporters, preventing sufficient
intracellular concentration—key translation issue. Also species
homolog differences can affect relevance.
Incorrect (B): In vitro enzyme inhibition does not guarantee
cellular activity due to ADME/transport/permeability barriers;
incubation time alone is an insufficient blanket explanation.
Incorrect (C): Buffer instability can occur but would usually
