GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1
Reference
Ch. Section I — Natural Products & Lead Identification
Stem
A 68-year-old patient with refractory atrial fibrillation’s plasma
shows anticoagulant activity after herbal supplement use. A
pharma team seeks a lead compound from the plant extract
responsible for the effect. Which initial experimental approach
best balances throughput and mechanistic insight to identify an
,active small-molecule lead while minimizing false positives from
complex mixtures?
Options
A. Whole-extract phenotypic screening in human iPSC-derived
cardiomyocytes.
B. Bioassay-guided fractionation combined with target-directed
enzymatic assays.
C. Direct high-throughput screening (HTS) of extract
constituents against purified ion channels.
D. In silico docking of all known plant metabolites to common
coagulation enzymes.
Correct answer
B
Rationale — Correct
Bioassay-guided fractionation isolates active fractions from
complex mixtures, then uses target-directed assays to link
activity to mechanism; this reduces false positives from matrix
effects and yields chemically tractable leads. It balances
empirical activity detection with mechanistic follow-up, ideal
when initial biological effect is known.
Rationale — Incorrect
A. Phenotypic screening can detect relevant biology but whole
extracts confound identification and are low throughput for
fractionation.
C. HTS of crude extracts against purified channels risks
interference from many constituents and lacks fractionation
,step to isolate actives.
D. In silico docking alone cannot account for unknown or novel
metabolites and won’t identify active concentrations or matrix
effects.
Teaching Point
Bioassay-guided fractionation links empirical activity to
isolatable chemical leads.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch.
Section I.
2
Reference
Ch. Section I — Target Identification & Validation
Stem
A biotech startup is developing an inhibitor for a novel kinase
implicated in chemotherapy-resistant lung cancer. Patient
tumors show heterogeneous expression; in vivo mouse models
with gene knockdown show partial tumour regression. What
constitutes the strongest next validation step to support the
kinase as a therapeutic target before large-scale lead
optimization?
Options
A. Demonstrate that pharmacologic inhibition of the kinase in
, patient-derived xenografts replicates knockdown effects.
B. Show in vitro that kinase overexpression increases
proliferation in a single cell line.
C. Sequence tumor samples to confirm absence of kinase
mutations.
D. Measure plasma levels of the kinase protein in healthy
volunteers.
Correct answer
A
Rationale — Correct
Pharmacologic inhibition in patient-derived xenografts directly
tests druggability and reproduces genetic knockdown effects in
a physiologically relevant model with tumor heterogeneity,
strengthening causal target-disease linkage before committing
to optimization.
Rationale — Incorrect
B. Overexpression in one line offers limited evidence and may
not reflect in vivo context.
C. Absence of mutations alone doesn’t validate causality or
therapeutic effect of inhibition.
D. Plasma protein levels in healthy volunteers are irrelevant to
target validation in tumors.
Teaching Point
Target validation requires pharmacologic replication of genetic
effects in clinically relevant models.
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1
Reference
Ch. Section I — Natural Products & Lead Identification
Stem
A 68-year-old patient with refractory atrial fibrillation’s plasma
shows anticoagulant activity after herbal supplement use. A
pharma team seeks a lead compound from the plant extract
responsible for the effect. Which initial experimental approach
best balances throughput and mechanistic insight to identify an
,active small-molecule lead while minimizing false positives from
complex mixtures?
Options
A. Whole-extract phenotypic screening in human iPSC-derived
cardiomyocytes.
B. Bioassay-guided fractionation combined with target-directed
enzymatic assays.
C. Direct high-throughput screening (HTS) of extract
constituents against purified ion channels.
D. In silico docking of all known plant metabolites to common
coagulation enzymes.
Correct answer
B
Rationale — Correct
Bioassay-guided fractionation isolates active fractions from
complex mixtures, then uses target-directed assays to link
activity to mechanism; this reduces false positives from matrix
effects and yields chemically tractable leads. It balances
empirical activity detection with mechanistic follow-up, ideal
when initial biological effect is known.
Rationale — Incorrect
A. Phenotypic screening can detect relevant biology but whole
extracts confound identification and are low throughput for
fractionation.
C. HTS of crude extracts against purified channels risks
interference from many constituents and lacks fractionation
,step to isolate actives.
D. In silico docking alone cannot account for unknown or novel
metabolites and won’t identify active concentrations or matrix
effects.
Teaching Point
Bioassay-guided fractionation links empirical activity to
isolatable chemical leads.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch.
Section I.
2
Reference
Ch. Section I — Target Identification & Validation
Stem
A biotech startup is developing an inhibitor for a novel kinase
implicated in chemotherapy-resistant lung cancer. Patient
tumors show heterogeneous expression; in vivo mouse models
with gene knockdown show partial tumour regression. What
constitutes the strongest next validation step to support the
kinase as a therapeutic target before large-scale lead
optimization?
Options
A. Demonstrate that pharmacologic inhibition of the kinase in
, patient-derived xenografts replicates knockdown effects.
B. Show in vitro that kinase overexpression increases
proliferation in a single cell line.
C. Sequence tumor samples to confirm absence of kinase
mutations.
D. Measure plasma levels of the kinase protein in healthy
volunteers.
Correct answer
A
Rationale — Correct
Pharmacologic inhibition in patient-derived xenografts directly
tests druggability and reproduces genetic knockdown effects in
a physiologically relevant model with tumor heterogeneity,
strengthening causal target-disease linkage before committing
to optimization.
Rationale — Incorrect
B. Overexpression in one line offers limited evidence and may
not reflect in vivo context.
C. Absence of mutations alone doesn’t validate causality or
therapeutic effect of inhibition.
D. Plasma protein levels in healthy volunteers are irrelevant to
target validation in tumors.
Teaching Point
Target validation requires pharmacologic replication of genetic
effects in clinically relevant models.
