GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1⃣
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Question (Stem)
A 62-year-old patient with chronic inflammatory pain is enrolled
in a translational NIH-funded program that screens
ethnobotanical extracts for novel COX-inhibitory compounds.
Your screening lab has identified a plant extract that inhibits
COX activity in a cell assay but shows cytotoxicity in hepatic cell
,lines. As lead discovery scientist, which next step most
appropriately balances identification of a valid lead versus early
safety concerns?
Options
A. Advance the crude extract directly into rodent efficacy
studies to see if therapeutic index is acceptable.
B. Fractionate the extract to isolate individual components and
retest fractions for COX activity and hepatotoxicity.
C. Discard the extract because any hepatic cytotoxicity in vitro
invalidates safety for systemic drugs.
D. Formulate the crude extract as a topical product to avoid
systemic exposure.
Correct answer
B
Rationale — Correct (B)
Fractionation isolates active constituents and separates toxic
components, allowing identification of a COX-inhibitory lead
with lower hepatotoxicity. This approach preserves
ethnobotanical signal while enabling structure elucidation, SAR
exploration, and targeted safety testing before in vivo studies.
Rationale — Incorrect
A. Advancing the crude extract risks animal welfare and
confounds interpretation because multiple compounds may
cause toxicity.
C. Early in vitro hepatotoxicity signals do not necessarily
preclude development; determining which component causes
,toxicity is required.
D. Topical use is a formulation workaround that may not
address systemic indications and still risks local toxicity without
characterization.
Teaching Point
Fractionate natural extracts early to separate active lead(s) from
toxic constituents.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2️⃣
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Question (Stem)
During high-throughput screening (HTS) of a 500,000-
compound library against a recombinant kinase target, one
chemotype repeatedly yields strong activity but also shows
promiscuous activity in many counter-screens. Which action
best addresses the risk of a frequent-hit (PAINS) chemotype
while preserving potential novel inhibitors?
Options
A. Label the chemotype as a pan-assay interference compound
and remove all analogs from the screening library.
, B. Perform orthogonal assays (e.g., orthogonal readouts and
biophysical binding assays) to verify target-specific engagement.
C. Increase compound concentration in the primary assay to
confirm potency.
D. Immediately progress the chemotype to medicinal chemistry
optimization because potency is high.
Correct answer
B
Rationale — Correct (B)
Orthogonal assays and biophysical methods (e.g., SPR, ITC)
differentiate true target engagement from assay artifacts
common to PAINS. Confirming specific binding before
dismissing or investing resources avoids false negatives and
prevents wasted optimization on artifacts.
Rationale — Incorrect
A. Blanket removal risks discarding genuine actives that share
substructures with PAINS; assessment is needed first.
C. Higher concentration exacerbates nonspecific effects and
increases false positives.
D. Optimizing a promiscuous chemotype wastes resources if
activity is artifact rather than target-directed.
Teaching Point
Use orthogonal binding assays to distinguish true hits from
PAINS before optimization.
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1⃣
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Question (Stem)
A 62-year-old patient with chronic inflammatory pain is enrolled
in a translational NIH-funded program that screens
ethnobotanical extracts for novel COX-inhibitory compounds.
Your screening lab has identified a plant extract that inhibits
COX activity in a cell assay but shows cytotoxicity in hepatic cell
,lines. As lead discovery scientist, which next step most
appropriately balances identification of a valid lead versus early
safety concerns?
Options
A. Advance the crude extract directly into rodent efficacy
studies to see if therapeutic index is acceptable.
B. Fractionate the extract to isolate individual components and
retest fractions for COX activity and hepatotoxicity.
C. Discard the extract because any hepatic cytotoxicity in vitro
invalidates safety for systemic drugs.
D. Formulate the crude extract as a topical product to avoid
systemic exposure.
Correct answer
B
Rationale — Correct (B)
Fractionation isolates active constituents and separates toxic
components, allowing identification of a COX-inhibitory lead
with lower hepatotoxicity. This approach preserves
ethnobotanical signal while enabling structure elucidation, SAR
exploration, and targeted safety testing before in vivo studies.
Rationale — Incorrect
A. Advancing the crude extract risks animal welfare and
confounds interpretation because multiple compounds may
cause toxicity.
C. Early in vitro hepatotoxicity signals do not necessarily
preclude development; determining which component causes
,toxicity is required.
D. Topical use is a formulation workaround that may not
address systemic indications and still risks local toxicity without
characterization.
Teaching Point
Fractionate natural extracts early to separate active lead(s) from
toxic constituents.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2️⃣
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Question (Stem)
During high-throughput screening (HTS) of a 500,000-
compound library against a recombinant kinase target, one
chemotype repeatedly yields strong activity but also shows
promiscuous activity in many counter-screens. Which action
best addresses the risk of a frequent-hit (PAINS) chemotype
while preserving potential novel inhibitors?
Options
A. Label the chemotype as a pan-assay interference compound
and remove all analogs from the screening library.
, B. Perform orthogonal assays (e.g., orthogonal readouts and
biophysical binding assays) to verify target-specific engagement.
C. Increase compound concentration in the primary assay to
confirm potency.
D. Immediately progress the chemotype to medicinal chemistry
optimization because potency is high.
Correct answer
B
Rationale — Correct (B)
Orthogonal assays and biophysical methods (e.g., SPR, ITC)
differentiate true target engagement from assay artifacts
common to PAINS. Confirming specific binding before
dismissing or investing resources avoids false negatives and
prevents wasted optimization on artifacts.
Rationale — Incorrect
A. Blanket removal risks discarding genuine actives that share
substructures with PAINS; assessment is needed first.
C. Higher concentration exacerbates nonspecific effects and
increases false positives.
D. Optimizing a promiscuous chemotype wastes resources if
activity is artifact rather than target-directed.
Teaching Point
Use orthogonal binding assays to distinguish true hits from
PAINS before optimization.
