Med Bio Exam 5

T/F: An IND must be filed with the FDA before the pre-clinical development phase

F

T/F: A first-in-class drug is one that uses a new/unique mechanism of action for treating a medical condition

T

T/F: The reverse chemical genetics small-molecule drug discovery pathway starts target validation.

T

T/F: A small molecule with a higher EC50 is more potent than a small molecule with a lower EC50 in the same bioassay.

F

T/F: The Ames test measures genome stability in response to exposure to drug

T

T/F: Histidine auxotrophs do not require histidine supplementation for cell growth.

F

T/F: Hydrogen donors are compounds which contain abstractable hydrogens located adjacent to heteroatoms such as oxygen, nitrogen, and sulfur.

T

T/F: The hydrogen acceptor is an electronegative atom of a neighboring molecule or ion that contains a lone pair that participates in hydrogen bonding.

T

T/F: Avastin (bevacizumab) is a small-molecule drug judged by its chemical name.

F

Which of the prefixes following describes an antibody-based biologic?

A. -mab

B. -bart

C. -vir

D. A & B

E. All the above

D

Which of the following describes a newly developed medication that is similar to a

pre-existing medication but is slightly modified with an improved safety profile?

A. First-in-class drug

B. Me-better drug

C. Orphan drug

D. Generic drug

E. None of the above

B

The pharmaceutical company AbbVie develops a new drug they name

"jayhawkanib." What can you assume about the function of the drug?

A. Artificial antibody

B. Targets factor Xa

C. Anti-viral

D. Small kinase inhibitor

E. None of the above

D

What is tested during Phase 2 of a clinical trial for a new drug?

A. efficacy

B. safety

C. large scale effects

D. long term effects

A

Which description best defines a me-better drug?

A. A drug that has improved profiles of side effects and activities

B. A drug that uses a unique mechanism of action for treating a medical condition

C. A drug that is developed to treat rare medical conditions

D. A drug that is created to be the same as an existing approved brand-name drug.

A

Which describes a drug with a low Kd?

A. The drug has a tighter interaction.

B. The drug is less likely to dissociate from its target

C. The drug binds to its target with high affinity.

D. The drug has a higher degree of selectivity for this target.

E. All of the above

E

Which statement is a false description of the LogP value?

A. LogP describes the distribution of a drug between octanal and water phases.

B. Average LogP value for existing FDA approve drugs is 2

C. LogP values range from 0 to 5

D. A high LogP value indicates the drug is hydrophilic.

D

Which statement is a false description of the P-glycoprotein (P-gp)?

A. P-gp is an efflux protein transporter

B. Minimal P-gp binding is required for a drug to pass the intestinal lumen to cells

C. P-gp drug binding is described using the LogP value

D. P-gp binding is measured using the MDR1-MDCK permeability assay

E. P-pg is present in the cell membranes of tissues including the intestine, kidney

and brain.

C

Which statement correctly describes reverse versus forward chemical genetics in the drug discovery process?

A. In phenotype-based drug screening (forward chemical genetics) the disease

target is unknown until after lead optimization.

B. When the target is validated and an assay is designed around it before

screening, the approach is target-based (reverse chemical genetics).

C. Both strategies are never used simultaneously; phenotype-based screening has

replaced target-based approaches due to lower attrition.

D. Forward chemical genetics requires prior knowledge of the target, whereas

reverse chemical genetics uses cell-death or regeneration readouts exclusively.

B

Which statement correctly interprets the therapeutic index and its relation to safety evaluation?

A. Therapeutic index is calculated as IC/CC; a lower number is preferred because it indicates the drug is more potent than toxic.

B. Therapeutic index is CC/IC; a higher number is better because it reflects a wider safety margin between efficacy and cytotoxicity.

C. The therapeutic index is irrelevant for PCC selection; only absolute potency

(lowest IC) determines advancement regardless of CC.

D. Drug potency and TI are compared solely by absorbance; fluorescence and

viability readouts are never used to generate dose-response curves.

B

Which scenario illustrates a phenotype-based (forward chemical genetics)

approach?

A. Designing an assay around a validated PD-1 target before screening, as with

Keytruda/Opdivo.

B. Screening for cell death or cell regeneration/wound-healing signals without prior knowledge of the molecular target.

C. Using CRISPR-Cas9 to edit the target gene before any compound screening.

D. Performing hit-to-lead SAR only after NDA approval

B

Lipinski's rules describe general qualities of orally active drugs. Which option

accurately lists the four rules and notes the empirical nature with exceptions?

A. ≤5 H-bond donors, ≤10 H-bond acceptors, molecular mass <500 Da, LogP ≤5;

these are strict requirements with no FDA-approved exceptions.

B. The "five" refers to five rules; smaller molecules always violate if LogP >2, as

seen with acetaminophen.

C. No more than 5 H-bond donors, no more than 10 H-bond acceptors, molecular

mass <500 Da, LogP ≤5; empirical rule with exceptions.

D. H-bond donors include CH groups; acceptors exclude S; rapamycin is an

exception because it has mass >500 Da only.

C

Which statement correctly explains the trade-off for high vs low Human Serum

Albumin (HSA) binding?

A. High HSA binding is always detrimental because it prevents target delivery; low binding is required regardless of potency.

B. High binding can be tolerated if the remaining free fraction is still effective at the target.

C. Drugs must have 100% free concentration in plasma; HSA binding eliminates plasma exposure entirely.

D. High HSA binding increases P-gp activity, making it ideal for BBB penetration.

B

Which scenario most correctly applies CC50, IC50, and therapeutic index to an

inhibitory anticancer lead?

A. Use EC50 for inhibition; CC50 in non-target cells; TI = EC50/CC50 (high

preferred).

B. IC50 for target inhibition; CC50 for cytotoxicity; TI = CC50/IC50.

C. CC50 replaces IC50 for inhibitors; TI should be <1 for drug-likeness.

D. Therapeutic index uses Kd/IC50; liver cells are irrelevant for oral inhibitors.

B

Which statement best captures a key trade-off in optimizing oral leads for potency, ADME, and safety?

A. Maximize LogP (>5) and HSA binding for plasma exposure; minimize therapeutic index to ensure efficacy.

B. Ignore Lipinski rules since exceptions like rapamycin prove they are irrelevant;

focus only on low Kd.

C. High P-gp activity is essential for BBB crossing; therapeutic index is secondary to Ames test results.

D. Aim for balanced LogP and high therapeutic index (CC50/IC50 or EC50), while maintaining low EC50/IC50 potency.

D

In hit-to-lead and lead optimization processes, which statement is true?

A. P-gp assay results in an important parameter to evaluate whether the drug will be permeable to the central nervous system.

B. If a compound is potent enough, the pharmaceutical company does not need to come up with a formulation for an oral drug to file an IND.

C. hERG binding affinity is an important indicator of membrane permeability.

D. Low plasma exposure is good for a lead compound, because serum albumin

binding will protect the drug from plasma proteases.

A

In oral drug development, the hits from HTS will have to go through intensive

optimization steps to become a PCC, costing more than 2 years and millions of

dollars. Why do drug companies or research institutes take these expensive

optimization steps? Choose the true statement.

A. In PCC optimization, most "red flag" toxicity problems (e.g., hERG ligands,

positives in Ames test) must be eliminated.

B. If the PCC is a PO drug, the metabolism of the drug (e.g., first-pass effect) must be carefully optimized. The Cmax of the PCC have to reach a certain threshold for the drug effectiveness.

C. The formulation of the drug is required to be optimized for maximizing the drug absorption.

D. Metabolic studies must be completed to optimize chemical stability.

E. All of the above.

E

In a phase partition experiment, the logP for drug A is 0.1. Which statement best

describes this drug?

A. This drug is hydrophilic.

B. This drug is very nonpolar.

C. This drug will prefer to bind tightly to cell membranes.

D. This drug will likely have a long half life.

A

What is the optimal LogP of an oral small-molecule drug?

A. -5

B. -2

C. 2

D. 6

C

An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance.

A. True

B. False

A

"Me-too" drug is a nickname of generic drug.

A. True

B. False

A

P-gp assay results can be used to evaluate whether the drug will likely be pumped out from epithelial cells into intestinal lumen.

A. True

B. False

D

Which of the following type patent is considered superior than others in protection scope for drug development?

A. Composition of matter

B. Manufacturing process

C. Formulation

D. Method of use

D

Which of the following is not a favorable pharmacokinetic property in small-molecule drug development?

A. Good aqueous solubility (> 100 µM)

B. Low toxicity (no toxicity observed at 50 ×IC50)

C. Very strong CYP450 inhibition (IC50 <10 nM)

D. Permeable in Caco-2 assay (> 1 ×10-6 cm-1)

C

Drug nomenclature suffixes

A. Small kinase inhibitor: ____________

B. Drug extracted from soil bacteria: ___________

C. Class of drugs with amide moiety: ________________

D. Derived from factor 10a, a key factor in anticoagulant action: __________

E. Antiviral drug: ____________

A. nib

B. cin

C. mide

D. ban

E. vir

Leads are typically developed into a __________________with the proper toxicity

and safety profile.

preclinical candidate

___________selective drugs affect mainly a single organ or system.

highly

Highly abundant blood plasma protein that binds to drugs is ___________________

human serum albumin

Which of the following best describes how cancer cells have acquired resistance to imatinib therapy?

A. Overexpression of P-gp transporters efflux imatinib too quickly for it to be

therapeutic.

B. T315 is replaced with isoleucine which lacks the hydroxyl group necessary

for the interaction with imatinib.

C. Cancer cells form more hinge regions to decrease the efficacy of imatinib.

D. Cancer cells have not yet developed resistance to imatinib.

B

Know how cancer cells have developed resistance to imatinib, how might this be

overcome?

A. Co-administer imatinib with P-gp inhibiting drugs.

B. Cancer cells have not yet developed resistance to imatinib.

C. Increase the dosage of imatinib as it lacks toxicity.

D. Development of me-too drugs such as ponatinib which have similar but

slightly different structures and functions allowing circumvention of

resistance.

D

Which of the following is true:

A. The Ames test measures the function of the Na/K pump

B. Kinases act to dephosporylate molecules

C. Tumors cannot develop drug resistance

D. MDR1 codes for P-gp, which is an important efflux transporter

D

Which of the following is NOT a quality that is preferred during hit-to-lead

optimization?

A. Low binding interactions with serum albumin

B. logP less than 5

C. Large Kd

D. Large therapeutic index

E. All of the above are preferred qualities

C

A large pharmaceutical company develops a new way to produce generic

Adderall which will rapidly increase manufacturing and production. What type of patent should this pharmaceutical company get?

A. Process patent

B. Method of use patent

C. Formulation patent

D. Composition of matter patent

A

Which of the following is false regarding CRISPR?

A. They detect and destroy DNA from similar bacteriophages during

subsequent infections

B. A side effect includes permanent gene-editing

C. They play a key role in the antibacterial defense system of prokaryotes

D. It includes "fixing" a short gene mutation

C

In hit-to-lead and lead optimization processes, which statement is TRUE?

A. P-gp assay results in an important parameter to evaluate whether the drug

will be permeable to the central nervous system.

B. If a compound is potent enough, the pharmaceutical company does not

need to come up with a formulation for an oral drug to file an IND.

C. hERG binding affinity is an important indicator of membrane permeability.

D. Generally speaking, low plasma exposure is good for a lead compound,

because serum albumin binding will protect the drug from plasma

proteases.

A

Which of the following biologics are not cell permeable?

A. RNA interference (RNAi)

B. Monoclonal antibodies (mAb)

C. Degrading Chimeras (PROTACs)

D. Antisense oligonucleotides (ASO)

E. CRISPR

B

Herceptin is a monoclonal antibody used to treat breast cancer. Which of the

following statements is false regaring Herceptin activity?

A. Herceptin acts by binding to Her-2 receptor and blocks receptor

dimerization.

B. Herceptin binding marks Her-2 receptor for degradation via the ubiquitin-

proteosome pathway

C. Herceptin marks the cancer cells for recognition by the immune system

D. Herceptin inhibits cellular signaling by binding to Her-2 receptor and is

internalized.

B

Why are liver microsomes considered the most critical biofluid for early stability

assessment of a small-molecule drug candidate?

A. They contain the highest concentration of plasma proteins that bind the

drug

B. They best mimic renal excretion pathways

C. They are the only biofluid that directly measures blood-brain barrier

penetration

D. The liver is the first metabolizing organ encountered after oral absorption

D

A lead compound shows very high intrinsic clearance in liver microsomes and excellent Caco-2 permeability. The most likely consequence for oral

bioavailability (%F) is:

A. Very high %F due to rapid absorption

B. Low %F primarily due to extensive first-pass hepatic metabolism

C. High %F if plasma protein binding is also high

D. No impact on %F

B

Unlike small-molecule drugs, monoclonal antibodies generally do not require assessment of:

A. Target binding affinity

B. Membrane permeability

C. Plasma half-life

D. Immunogenicity

B

In the HER2 signaling pathway, the critical step for initiating the downstream

cascade is:

A. Monomer stabilization

B. Receptor dimerization (homo- or hetero-)

C. Ligand-independent internalization

D. Proteolytic cleavage

B

CRISPR is best described as an:

A. RNA-dependent DNAse

B. Protein degradation tag

C. Small-molecule inhibitor

D. Antibody-based recruiter

A

Regarding Lipinski's Rule of Five, PROTACs fits how many of the four main

criteria?

A. All four (MW <500 Da, H-donors ≤5, H-acceptors ≤10, logP ≤5)

B. Only two (e.g., H-donors =2 ≤5, but MW >500 Da from 8 rings at 80 Da

each, H-acceptors >10)

C. None

D. Three

B

Which of the following statements is true for kinases?

A. Kinase inhibitors facilitate phosphate transfer so that the reactions can go

faster.

B. Kinase inhibitors may bind to the ATP- or substrate-binding site.

C. The adenosine group on ATP is transferred to the substrate peptide or

protein.

D. Phosphorylation is an irreversible reaction.

E. None of the above.

B

The first step of producing monoclonal antibodies in drug discovery is usually __.

A. Development of a bioassay

B. HTS of antibody libraries

C. Virtual screening

D. Animal immunization with the target antigen

D

Which of the following statements is true about gene therapy?

A. RNA interference (RNAi) is a gene therapy approach that permanently

silences or knocks down the expression of disease-causing genes.

B. Gene therapies, which involve the transfer of genetic material into cells, can potentially trigger cytokine storm if the transferred genes stimulate a strong

immune response.

C. The ADRs of gene therapies are the same between young patients and the

elderly.

D. Gleevec is a treatment of a genetic disorder (Bcr-Abl fusion) and, therefore,

is regarded as gene therapy.

E. None of the above.

B

Which statement about monoclonal antibodies is true?

A. Antibodies will not experience a first-pass effect in their metabolism.

B. A monoclonal antibody molecule has 2 heavy chains and 4 light chains.

C. Epitopes usually bind to the F(ab) domain of a monoclonal antibody.

D. Monoclonal antibodies can target the intracellular domain of target proteins.

E. None of the above.

C

Which statement is true about 1st, 2nd, and 3rd generations of Bcr-Abl

inhibitors?

A. The drug metabolism pathways among these Bcr-Abl inhibitors may be

different.

B. The selectivity of these drugs over other kinases are the same.

C. Imatinib can overcome drug resistance derived from T315I mutation on Abl.

D. These molecules are all have action-dependent catalytic mechanisms as

their drug effect.

A

Which of the following is true regarding development of monoclonal antibodies?

A. The hybridoma fusion cell is both immortal and has a rescued ability to

synthesize DNA.

B. T cells are isolated from mice spleen for fusion with myeloma cells.

C. Myeloma cells die because they are not immortal.

D. Hypoxanthine-aminopterin-thymidine (HAT) media promotes the growth of

myeloma cells.

A

Dasatinib is a small-molecule drug that binds and inhibits several kinases. The

dissociation constant (Kd) of dasatinib and epidermal growth factor receptor

(EGFR) is 17 nM. The Kd of dasatinib and Bruton's tyrosine kinase (BTK) is 0.85

nM. The binding affinity of dasatinib and 1 (EGFR or BTK?) is higher.

BTK

What is the MoA of Herceptin (trastuzumab)?

A. Herceptin binds to Her2 and inhibits Her2 dependent pathways, such as

PI3K and RAS pathways

B. Herceptin disrupts the interaction of Her2 and Her1-4

C. Herceptin-Her2 complex is internalized by endocytosis and degraded by

lysosomal pathway

D. All of the above

D

Which of the following statement is incorrect in describing gene therapies?

A. Gene therapies deliver nucleic acid into human cells.

B. RNAi greatly increases the protein level of the target gene.

C. CRISPR is a gene-editing method which can potentially "fix" a mutation of a gene.

D. RNAi are double-stranded RNAs (e.g., hairpins or two annealed RNA

strands).

B

A prodrug can be best described as:

A. A drug that has been shown effective in phase 2 of clinical development that can then be moved for testing in phase 3 on a larger scale of test subjects.

B. A drug that is inactive in the body that when metabolized becomes active

C. A prototype drug that is first in its class, or the first generation of its kind (for example, imatinib is the prodrug of ponatinib)

B

Which of the following is not a xenobiotic?

A. 1,2-butadiene

B. Caffeine

C. Porcine small intestinal submucosa

D. Penicillin

E. D-glucose

E

Which of the following is a key function of xenobiotic metabolism?

A. Modification of specific functional groups

B. Converting exogenous chemicals to more water-soluble compounds

C. Increase the polarity of exogenous chemicals

D. Aid elimination of exogenous chemicals from the body

E. All of the above

E

Remdesivir is an anti-SARS-CoV-2 drug developed by Gilead. The current

emergency use of remdesivir in the US has shown some promising results for

patients with severe COVID-19. Based on the knowledge you have learned in the

class, determine whether the following statements are T/F.

1. Remdesivir is a prodrug and is administered intravenously (IV). It means that Remdisivir is probably metabolized to yield the active drug form in the plasma.

2. The active form of remdesivir selectively inhibits the viral RNA polymerase in

coronavirus. This indicates the activity of remdesivir on human RNA polymerases

is relatively low which is desirable to minimize potential toxicity.

Responses:

A. both true

B. both false

C. only the first statement is true

D. only the second statement is true

A

In the prodrug strategy, one intentionally uses an _____________ (inactive or

active) moiety that is removed by metabolism to generate the _____________

(inactive or active) drug species.

inactive, active

Phase I and Phase II reactions are mainly carried out by enzymes in which

cellular compartment, respectively?

A. Smooth endoplasmic reticulum, Lysosome

B. Nucleus, Mitochondria

C. Outer Cell Membrane, Cytosol

D. Mitochondria, Smooth Endoplasmic Reticulum

E. Smooth Endoplasmic Reticulum, Cytosol

F. Cytosol, Mitochondria

E

The primary mechanism of the acetaminophen-warfarin interaction is:

A. Acetaminophen competitively inhibits CYP enzymes involved in warfarin

metabolism

B. Warfarin induces CYP enzymes that metabolize acetaminophen faster

C. Direct binding to vitamin K receptors

D. Increased absorption of both drugs

A

The Phase II metabolism required for efficient THC excretion after initial

oxidation:

A. Another oxidation step

B. Glucuronidation to add a sugar moiety

C. Sulfation only

D. Methylation

B

The warfarin-acetaminophen interaction increases bleeding risk because

acetaminophen:

A. Induces CYP enzymes that activate warfarin

B. Competitively inhibits the CYP-mediated metabolism of warfarin

C. Displaces warfarin from albumin binding sites only

D. Increases vitamin K absorption

B

Inhibition of drug-metabolizing enzymes (e.g., CYP450) generally results in:

A. Decreased drug concentration and loss of efficacy

B. Increased drug concentration and potential toxicity

C. Accelerated Phase II conjugation

D. No change in half-life

B

Age-related changes in drug half-life:

A. Always dramatically increase half-life in the elderly due to universal decline in

metabolism

B. Do not play a role in all cases

C. Only affect Phase I reactions

D. Eliminate first-pass effect entirely

B

Which of the following statements is true about the first-pass effect?

A. The first-pass effect is only applicable to IV drugs.

B. Morphine is active as an oral drug and, therefore, there is no first-pass effect on

this drug.

C. First-pass metabolism activates remdesivir.

D. The first pass effect can be circumvented by changing PO into IV administration.

E. None of the above.

D

Which of the statements about drug metabolism is true?

A. The liver is the major metabolizing organ for all drugs.

B. The intestine can be the major metabolizing organ for some IV drugs.

C. Phase I metabolism in liver always make a drug more hydrophilic and inactive.

D. Changes to intestinal flora does not affect drug metabolism.

E. None of the above (A-D are all false).

E

Remdesivir is an anti-SARS-CoV-2 drug developed by Gilead. Based on the

knowledge you have learned in the class, which of the following statement is

TRUE?

A. The desired therapeutic index for Remdesivir during hit-to-lead optimization was low.

B. Remdesivir is a prodrug. The ester bond in the molecule is probably cleaved by

plasma esterases.

C. The active form of remdesivir inhibits the RNA polymerase in coronavirus. The Kd value of the active form of remdesivir and viral RNA polymerase is probably

higher than the Kd value of remdesivir binding with human RNA polymerases.

D. Remdesivir has a matter of composition patent held by Gilead. If someone else invents a way to produce remdesivir, this person can file a process patent and found a company to produce this drug pills.

E. None of the above.

B

Remdesivir is an anti-SARS-CoV-2 drug developed by Gilead. Determine

whether the following statements are T/F.

A. Remdesivir undergoes an esterase reaction before becoming an active

nucleoside.

B. The active form of remdesivir selectively inhibits the coronavirus RNA

polymerase over human RNA polymerases.

C. Hydrolysis of remdesivir is the key final metabolic step before inhibition of viral RNA replication.

A. True

B. True

C. True