PHRM 460 FINAL EXAM STUDY GUIDE
A QSAR was developed from the IC50 values measured for 21 compounds using a
cell-based assay. This QSAR was used to predict the activity of three ligands and the
results are rather disappointing; the predicted IC50 values differ by more than 1000-fold
from the measured values What do you conclude? - ANSWER The three ligands may not
be similar in chemical structure to the training set for the QSAR model.
Ligand-based and structure-based pharmacophore modeling involves - ANSWER
alignment in three dimensions of known ligands to maximize overlap of groups with the
same chemical property
A goal of computationally modeling small molecules binding to a protein is to predict
relative free energies of binding. Free energy includes contributions from both enthalpy
and entropy. Which statement most accurately describes these thermodynamic
parameters? - ANSWER all of the above
Enrichment Factor - ANSWER E=(Nfound/#top rank)/(Nact/# in database)
Virtual screening is best described by which statement? - ANSWER Virtual screening
based on a pharmacophore model tries to match a number of chemical features
arranged in a certain 3-dimensional pattern.
In the last 20 years, attrition due to the following reason has been reduced markedly -
ANSWER Pharmacokinetics
A prodrug strategy is one means to improve solubility for parenteral preparations -
ANSWER True
Avastin (bevacizumab) by Genentech is one of the highest selling monoclonal
antibodies. The source of this antibody is - ANSWER Humanized
Major problem of NSAIDs today - ANSWER GI bleeding
What was the biggest problem with the introduction of oral non-vitamin K antagonist
anticoagulant when introduced onto the market? - ANSWER Lack of antidote to reverse
the effects
Which of the following would be important to include in the case statement for unmet
medical need supporting the discovery of new oral anticoagulants? - ANSWER Reduce
frequency of lab monitoring for patients
How many deaths in the US are due to blood clots each year? - ANSWER 100,000
Rationale for developing COX-2 selective inhibitors included - ANSWER A& B are
correct
, What is the primary strategy behind the use of combination drugs to treat Hepatitis C
viral infection? - ANSWER Reduce likelihood of drug resistance
Most costly phase of drug discovery and development is - ANSWER Pase 2 & 3 clinical
trials
Primary aim of a drug as a therapeutic - ANSWER minimize disvalue associated with a
unmet need
Therapeutic effectiveness and Benefit refers to - ANSWER Measure of drug action as it
affects populations and society at large
What is not a component of disease? - ANSWER Prognosis of recovery
A manhattan plot - ANSWER Used in GWAS
A target-based screen is most likely to be successful in identifying lead compounds that
eventually become drugs when - ANSWER seeking to improve the efficacy of an existing
drug.
GWAS - ANSWER links SNPs to a disease or condition
a disadvante of screens using phenotypic assays is that - ANSWER the compounds may
have non-specific, off-target effects
For which of the following screens might you use a focused chemical library - ANSWER
a screen for inhibitors of a kinase implicated in inflammatory bowel disease
How would you evaluate whether an assay is likely to be sensitive enough to use in a
HTS - ANSWER Measure the IC50 of a known inhibitor in your assay and compare the
value you get to published results
A characteristic of an allosteric antagonist could be detected - ANSWER in
dose-response curves using ligand displacement assay where the maximal antagonist
concentration cannot fully displace all of the ligand
During lead optimization phase, a series of cell-based assays were executed. The IC50
for inhibition of cell growth using a primary tumor cell-based assay with Lead drug A
was 1.4 µM. When the assay was executed again but the test drug was pre-incubated in
human serum for 10 minutes before adding to the tumor cell culture, the IC50 value for
the drug effect on cell proliferation was shifted to 100 µM. What is a possible explanation
for this observation? - ANSWER The lead drug A is primarily metabolized in the serum to
an inactive agent before uptake by the tumor cells
In the case of testing a new drug target the drug lead candidates will be evaluated using
ex vivo models to evaluate if - ANSWER the drug engages the protein by using
downstream effects as a biomarker
Of the following statements about potency for the drug-target interaction, which would
A QSAR was developed from the IC50 values measured for 21 compounds using a
cell-based assay. This QSAR was used to predict the activity of three ligands and the
results are rather disappointing; the predicted IC50 values differ by more than 1000-fold
from the measured values What do you conclude? - ANSWER The three ligands may not
be similar in chemical structure to the training set for the QSAR model.
Ligand-based and structure-based pharmacophore modeling involves - ANSWER
alignment in three dimensions of known ligands to maximize overlap of groups with the
same chemical property
A goal of computationally modeling small molecules binding to a protein is to predict
relative free energies of binding. Free energy includes contributions from both enthalpy
and entropy. Which statement most accurately describes these thermodynamic
parameters? - ANSWER all of the above
Enrichment Factor - ANSWER E=(Nfound/#top rank)/(Nact/# in database)
Virtual screening is best described by which statement? - ANSWER Virtual screening
based on a pharmacophore model tries to match a number of chemical features
arranged in a certain 3-dimensional pattern.
In the last 20 years, attrition due to the following reason has been reduced markedly -
ANSWER Pharmacokinetics
A prodrug strategy is one means to improve solubility for parenteral preparations -
ANSWER True
Avastin (bevacizumab) by Genentech is one of the highest selling monoclonal
antibodies. The source of this antibody is - ANSWER Humanized
Major problem of NSAIDs today - ANSWER GI bleeding
What was the biggest problem with the introduction of oral non-vitamin K antagonist
anticoagulant when introduced onto the market? - ANSWER Lack of antidote to reverse
the effects
Which of the following would be important to include in the case statement for unmet
medical need supporting the discovery of new oral anticoagulants? - ANSWER Reduce
frequency of lab monitoring for patients
How many deaths in the US are due to blood clots each year? - ANSWER 100,000
Rationale for developing COX-2 selective inhibitors included - ANSWER A& B are
correct
, What is the primary strategy behind the use of combination drugs to treat Hepatitis C
viral infection? - ANSWER Reduce likelihood of drug resistance
Most costly phase of drug discovery and development is - ANSWER Pase 2 & 3 clinical
trials
Primary aim of a drug as a therapeutic - ANSWER minimize disvalue associated with a
unmet need
Therapeutic effectiveness and Benefit refers to - ANSWER Measure of drug action as it
affects populations and society at large
What is not a component of disease? - ANSWER Prognosis of recovery
A manhattan plot - ANSWER Used in GWAS
A target-based screen is most likely to be successful in identifying lead compounds that
eventually become drugs when - ANSWER seeking to improve the efficacy of an existing
drug.
GWAS - ANSWER links SNPs to a disease or condition
a disadvante of screens using phenotypic assays is that - ANSWER the compounds may
have non-specific, off-target effects
For which of the following screens might you use a focused chemical library - ANSWER
a screen for inhibitors of a kinase implicated in inflammatory bowel disease
How would you evaluate whether an assay is likely to be sensitive enough to use in a
HTS - ANSWER Measure the IC50 of a known inhibitor in your assay and compare the
value you get to published results
A characteristic of an allosteric antagonist could be detected - ANSWER in
dose-response curves using ligand displacement assay where the maximal antagonist
concentration cannot fully displace all of the ligand
During lead optimization phase, a series of cell-based assays were executed. The IC50
for inhibition of cell growth using a primary tumor cell-based assay with Lead drug A
was 1.4 µM. When the assay was executed again but the test drug was pre-incubated in
human serum for 10 minutes before adding to the tumor cell culture, the IC50 value for
the drug effect on cell proliferation was shifted to 100 µM. What is a possible explanation
for this observation? - ANSWER The lead drug A is primarily metabolized in the serum to
an inactive agent before uptake by the tumor cells
In the case of testing a new drug target the drug lead candidates will be evaluated using
ex vivo models to evaluate if - ANSWER the drug engages the protein by using
downstream effects as a biomarker
Of the following statements about potency for the drug-target interaction, which would
