BITG0902: Drug Design, Discovery, Delivery, and Theranostics Practice Questions

Answer the following questions in your own words

1. A. Suppose you have joined a pharmaceutical company that is actively engaged in developing new
drug entities for various hematological malignancies. The drug development unit in your company
is classified into the following teams.

i) Drug discovery project team.

ii) Preclinical drug development project team,
iii) Clinical drug development project team.

Based on your knowledge of drug design and discovery roadmap, answer the following questions:

a. Are the terms “drug design” and “drug discovery” synonymous? Explain.

b. A is a molecule within the living body that is associated with a particular disease process. A can
interact with an endogenous ligand or a drug molecule to produce the desired therapeutic effects. B
is a molecule that shows the desired biological activity in a screening assay. C is a molecule that
exhibits biological or pharmacological properties with therapeutic characteristics. What is the
relationship between A, B and C?

c. A key responsibility of your project team is to identify B and C. Which team do you think you will
be in?

d. While developing a new drug, which way should you go: B → C or C → B?

e. In the drug discovery process, once the lead is identified, is it necessary to optimize the lead? If yes,
which parameters should you consider while optimizing the lead?

f. You want to test the biological efficacy of a newly synthesized drug molecule. What should be your
next step?

g. What do you mean by in vitro, in vivo, ex-vivo, and in-silico studies? In which stages of the drug
discovery process are they involved?

h. What is ADME? How does it fit into drug development?

i. You need to find the elimination half-life of a new drug molecule. Should you conduct
pharmacokinetic or pharmacodynamic studies? If you want to check the efficacy of the drug
molecule, what type of study would you conduct?

j. What is a Phase I clinical trial?

k. What is Phase IIa and Phase IIb clinical trial?

l. What is the difference between Phase III and Phase IV clinical trial?

m. Following successful clinical trial of a newly discovered drug, your company seeks to get formal
approval for marketing the drug in the United States (US). You have been asked to prepare the
relevant documents for submission to FDA. Which document would you submit to FDA: NDA or
BLA or both?

n. In what circumstances would you file the following applications: i) NDA; ii) ANDA and iii) BLA.
BITG0902: Drug Design, Discovery, Delivery, and Theranostics Practice Questions

o. Suppose a new drug gets FDA approval and necessary authorization for marketing in the US. After
marketing the drug, some potential safety concerns are noted. Is there any way to address the
adverse effects associated with an FDA-approved drug that is already in the market?

2. The phenylalkylamine, Cinacalcet, is an oral calcimimetic agent used for the treatment of secondary
hyperparathyroidism, parathyroid carcinoma-associated hypercalcemia, and severe hypercalcemia
associated with primary hyperparathyroidism. Instead of binding to the Ca2+ binding pocket located
in the large extracellular domain of the calcium-sensing receptor (CaSR), Cinacalcet binds to the
transmembrane region of CaSR. This particular mode of binding leads to a different structural
configuration that is more sensitive to serum calcium. Subsequently, the serum parathormone
(PTH) is reduced at lower levels of serum calcium. Based on the proposed mechanism of action,
determine whether Cinacalcet is an orthosteric or allosteric drug.

3. Carefully inspect the structure of the drug molecules provided below. Looking at the structures, can
you comment on its therapeutic use and mechanism of action?

4. Suppose you are diagnosed with hypertension and the doctor has prescribed you verapamil, to be
taken after your breakfast. Can you drink grapefruit juice for your breakfast? Which medicine with
a similar mechanistic pathway do you think would be a safer option if you want to keep grapefruit
juice in your daily diet? If doctor prescribes you Enalapril instead of Verapamil, do you think it
would act following the same pharmacology or mechanistic pathway? Explain.
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5. There are two major types of drug design: Structure-based Drug Design (SBDD) and Ligand-
based Drug Design (LBDD). Please visit this link https://axispharm.com/drug-development-
virtual-screening-molecular-docking-qsar/ to develop a preliminary concept on these two basic
methods of computer-aided drug design (CADD) applied in modern drug discovery and
development. Answer the following questions based on your knowledge of SBDD and LBDD.

a. What are the key differences between SBDD and LBDD?

b. What is the difference between a drug and a ligand?

c. What is a pharmacophore?

d. What do you mean by virtual screening in drug development? Can virtual screening be used for
evaluating the ADME/ toxicity of potential drug candidates?

e. What is high-throughput screening in drug discovery?

f. Why is molecular docking used in SBDD?

BITG0902: Drug Design, Discovery, Delivery, and Theranostics Practice Questions

g. What is the scoring function in molecular docking?

h. Can you name a few FDA-approved drugs that were identified by SBDD?
i. Is QSAR used in SBDD or LBDD?

j. Who is the founder of QSAR?

k. What is the importance of QSAR used in drug design?

l. What are the basic principles of QSAR model validation?

m. What are the methods used in QSAR?

n. There are two types of QSAR models: i) Statistical-based models and Expert rule-based models.
What are the key differences between these two models?

o. How do you calculate the QSAR?

p. What are the three QSAR parameters?

q. Is there any limitation of QSAR?

r. What is Lipinski’s rule of five or Pfizer’s rule of five (R05) in drug design?

s. Can you name a few commercially available CADD software packages?

6. a. You have a compound library comprising around 10000 chemical compounds. Explain how using
high throughput screening you can identify the potential drug candidate from such a huge collection
of compounds.

b. Virtual drug screening refers to a computational approach that is used to predict drug activity by
fitting chemical structures to targets. Such screening is commonly used to rapidly test a library of
probable drug candidates for their potential to bind and inhibit a particular enzyme or receptor-
based target. As of now, there are two broad categories of screening techniques: i) structure-based
and ii) ligand-based. If you are not aware of the 3d structure of the target, which method will you
use? Explain how using your chosen method, you can identify the potential drug candidate.

c. Why are molecular descriptors used in QSAR? Give one example each of 1D, 2D, and 3D
descriptors.

d. Why do we need to remove PAINS during high-throughput screening?

e. While developing a new drug entity, numerous impurities may be associated with the API during
the manufacturing process. Can you apply QSAR models to predict the mutagenic potential of the
associated impurities?

f. Currently, a host of artificial intelligence (AI) tools are being used to revolutionize the different
stages of the drug discovery process. These AI tools hold tremendous potential to expedite the speed
and cut down the cost of new drug discovery. Suppose you are working in a pharmaceutical
company that specializes in oncology drug development. Can you use AI approaches for exploring
novel anticancer targets? Explain.
BITG0902: Drug Design, Discovery, Delivery, and Theranostics Practice Questions

g. The chemical structures of various cyclooxygenase 2 (COX2) inhibitors are furnished below.
Explain how using these structures you can develop a QSAR model for the evaluation of the best
structure-activity correlation.

h. In February 2023, the FDA granted orphan drug designation to INS018_055. What is
INS018_055? Why is it designated as an orphan drug?

i. Omeprazole is a well-known medication used to treat or combat gastroesophageal reflux

disease (GERD). The structure of Omeprazole is given below. Looking at the structure, predict
whether Omeprazole will conform to Lipinski’s rule of 5. Justify your predictions with proper
reasonings.

j. How can you define lead-like compounds based on the rule of three? Explain.
BITG0902: Drug Design, Discovery, Delivery, and Theranostics Practice Questions

7. a. Nicotinic Acetylcholine Receptor is an ionotropic receptor whereas muscarinic acetylcholine and

glutamate receptors are examples of metabotropic receptors. What is the key difference between an
ionotropic and metabotropic receptor?

b. Both captopril and amlodipine are used to treat hypertension. Do they work in the same way?

c. Suppose one of your family members is suffering from hypertension and he/she is advised by
the doctor to take Enalapril – a prodrug belonging to the class of ACE inhibitor drugs. Explain
stepwise how an ACE inhibitor like Enalapril helps to reduce blood pressure in hypertensive
patients. If the doctor had prescribed Nifedipine instead of Enalapril, would it act in the same way?
Explain with proper reasoning.

d. Can you explain why more than 30% of FDA-approved drugs target GPCRs? Give an example
of a GPCR-targeting drug that is used to treat gastroesophageal reflux disease (GERD).

e. Both Cimetidine and Levocetirizine are known to target the histamine (H) receptors. Yet,
Cimetidine is an anti-ulcer agent (GERD medication) while Levocetirizine is used to treat the
symptoms of various allergies. Explain why these two drugs exhibit different pharmacological
activities.

f. Amphogel is an antacid - Explain how it works. Suppose you are suffering from gastroesophageal
reflux disease. Between Ranitidine and Omeprazole, which one do you think will provide stronger,
and longer lasting relief? Explain in the light of mechanism of action of these two drugs.

g. Cisplatin is a platinum-based chemotherapeutic agent used to treat a

variety of cancers, including sarcomas, some carcinomas (e.g., small cell
lung cancer, and ovarian cancer), lymphomas, and germ cell tumors.
Based on its mechanism of action, it falls under the class of alkylating
agent. The structure of Cisplatin is given as follows.

i) Which of the four ligands coordinated to central platinum will be replaced by water
following the cellular uptake of the drug?
ii) Explain mechanistically, how Cisplatin binds to the nucleobase of the DNA.

h. Doxorubicin is an anticancer drug that was approved by the FDA

in 1974 to treat a variety of cancers, including the breast, lung,
gastric, ovarian, thyroid, non-Hodgkin’s, and Hodgkin’s
lymphoma, multiple myeloma, sarcoma, and pediatric cancers.

i) Carefully review the chemical structure of Doxorubicin and

explain how it intercalates into DNA.
ii) Can Doxorubicin be classified as a topoisomerase inhibitor? Justify your answer with
proper reasoning.
iii) Doxorubicin also exerts its anticancer activity through free radical generation, which causes
damage to cellular membranes, DNA, and proteins – Looking at the structure of
Doxorubicin, can you explain how it releases reactive oxygen and nitrogen species?
BITG0902: Drug Design, Discovery, Delivery, and Theranostics Practice Questions

iv) Is it safe to prescribe Doxorubicin chemotherapy to patients with poor heart function?
Explain briefly.

i. Both Doxorubicin and Paclitaxel are used for the treatment of advanced breast cancer – Do they
fall under the same BCS class? Unlike Doxorubicin, Paclitaxel is a microtubule-targeting
anticancer drug – How do you think will Paclitaxel inhibit cancer cell proliferation?

j. Doxil is the first FDA-approved nano-drug (1995). for the treatment of ovarian cancer, acquired
immune deficiency syndrome (AIDS)-related to Kaposi's Sarcoma, and multiple myeloma. Is
there any advantage of Doxil over free Doxorubicin? Which of the two formulations is expected
to demonstrate a lower cardiotoxicity?

k. The oral bioavailability of paclitaxel and docetaxel are 1% and <10%, respectively, whereas
for doxorubicin the value is <5% - Explain why most anticancer drugs have poor
bioavailability. Suppose you are a part of the formulations team in a leading pharmaceutical
company that specializes in oncology medicines. Your team leader has given you the
responsibility to come up with a formulation that can enhance the oral bioavailability of
doxorubicin and thereby, enhance and augment its anticancer efficacy.

l. Standard formulation of paclitaxel is composed of solvents, such as Cremphor-EL – What do

you think are the advantages of nab-Paclitaxel over Cremophor – EL- Paclitaxel? Will nab-
Paclitaxel and Cremophor-EL-Paclitaxel exhibit the same tumor accumulation? Justify your
answer with appropriate reasoning.

m. Match the following:

Column A Column B
Doxorubicin Folate receptor antagonist
Paclitaxel Selective estrogen receptor antagonist
Methotrexate Alkylating agent
Tamoxifen Anthracycline antibiotic
Cisplatin Microtubule inhibitor

8. a. Levoflox 500 is an antibiotic, used to treat bacterial infections. Each tablet contains 500 mg of
Levoloxacin. The molecular weight of Levofloxacin is 361.368 g/ml. If there are approximately
1013 cells in our body, do you think we require the entire 500 mg of the drug to kill much lesser
number of infected cells in our body? Explain.

b. Bare or unmodified nanoparticles are prone to aggregation which makes them unstable and
unsuitable for further applications – Suggest a strategy that can be used to prevent the
aggregation/coagulation of nanoparticles during colloidal synthesis.

c. Opsonization is one of the most important barriers to controlled drug delivery. Because
nanoparticles are regarded by our body as foreign particles, opsonins bind to their
surfaces resulting in their phagocytosis. Can you suugest a strategy to reduce
nanoparticle opsonization?

d. Following i.v. administration, NPs are cleared up within minutes from the bloodstream
– What do you think will be there final biodistribution?
BITG0902: Drug Design, Discovery, Delivery, and Theranostics Practice Questions

e. In the brain, endothelial cells and reinforcing astrocyte cells restrict the level of pinocytosis
through the formation of tight junctions between cells at the blood-brain interface. This results
in the formation of a structural and metabolic barrier, commonly referred to as the blood-brain
barrier (BBB) – Can you suggest a strategy by which a nano-drug delivery system can overcome
the BBB?

f. Liposome-based mRNA anti-COVID-19 vaccine has been created by Pfizer/BioNTech and

Moderna – What are the advantages of using liposomes to deliver mRNA into cells?

g. The virus causing COVID-19, SARS-CoV-2, enters our body via droplets or aerosols that get
into our nose, mouth or eyes. Based on this information, try to explain what type of vaccine
you would prefer for COVID-19: an injected vaccine or nasal vaccine.

h. Polymeric nanocarriers based on Poly (lactic-co-glycolic acid) (PLGA) are highly attractive
candidates for oral drug delivery. Drug loaded PLGA nanoparticles have been extensively
studied and have been reported to enhance the oral bioavailability, and efficacy of the
encapsulated drug molecule. Based on your knowledge of the mechanism of oral drug
absorption, rationalize this finding.

9. a. Majority of the patients admitted to a hospital with severe infections are initially started with
intravenous (i.v.) medications. Based on your understanding of ADME, can you rationalize why
the drugs are administered via i.v. route given that oral delivery is more patient-compliant and
economical method of administration?

b. Based on your understanding of ADME, explain what type of problems can arise with drugs
that are highly protein bound such as warfarin.

c. Codeine, a weak narcotic pain reliever and cough suppressant, is a prodrug that must be
metabolized to its active metabolites, morphine and codeine 6-glucuronide, to be
effective. Cytochrome P450 2D6 (CYP2D6) is an enzyme that converts codeine into morphine
to provide its analgesic effect. Based on your understanding of ADME, explain whether the
genetic variations in CYP2D6 will impact the pharmacology of codeine across patients.

d. A patient with adverse reaction to Drug X requires that the plasma drug concentration not ever
exceed 40 mg/L. If Drug X has half-life of 8 hrs and clearance of 4 L/hr, what do you think is
the best i.v. loading dose that will give the maximum blood levels while avoiding the adverse
reaction? Choose the correct answer and justify your choice with proper reasonings.

i) 2500 mg
ii) 2200 mg
iii) 2000 mg
iv) 1700 mg
v) 1000 mg
[ Answer Hints: Use the formula: t1/2 = ln (2)/λ = ln (2) ∗Vd/CL = 0.693∗Vd /CL to calculate Vd where,
Vd = volume of distribution; CL = clearance; λ = elimination rate constant = CL/Vd.

Calculate the maximum amount of drug that can be loaded using the following equation: Volume of
Distribution (Vd) = Amount of drug in the body (mg) / Plasma concentration of drug (mg/L).

Your best i.v. loading dose while avoiding adverse effects should not exceed the maximum loading
dose but close to it. ]
BITG0902: Drug Design, Discovery, Delivery, and Theranostics Practice Questions

10. a. Feridex® and Ferumoxytol are two different iron oxide-based MRI contrast agents. The DLS
size of Feridex® is 120-180 nm and that of Ferumoxytol is 30 nm. Between these two formulations
which one will you prefer for – i) liver imaging; ii) metastatic lymph node imaging; iii) cellular
imaging and iv) cerebral blood volume MRI?

b. Ferristene Abdoscan® is an iron-oxide based MRI contrast agent with DLS size greater than
300 nm. It is used for gastrointestinal imaging. Which delivery route will you prefer for the
contrast agent?

c. FLASH-3D images of a mouse brain captured at 100 µm3 spatial resolution before and after
the injection of an MRI contrast agent A are provided as follows.
Pre-contrast Post-contrast

i) Looking at the images, can you identify whether A is a T1- or T2 - weighted contrast agent?
Explain.
ii) What are the key differences between a T1- and T2- weighted contrast agent?
iii) How does MRI modality differentiate between body tissues?
iv) Which tissue-specific parameters influence the contrast in an MRI image?

d. A and B represents the in vivo hippocampal R2* signal changes of a rat brain administered with
two different variants of carboxymethyl dextran coated iron oxide nanoparticles: CION-A and
CION-B. Both contrast agents were administered 15 min after the onset of the MRI scan and
the changes in contrast signal as function of time is shown below. What would be your inference
about the pharmacokinetic profile of CION-A and CION-B? Based on their pharmacokinetic
profile, which of these two contrast agents would you think is preferrable for cerebral blood
volume (CBV)- weighted functional MRI (fMRI) and high-resolution MR angiography?

B 120

100
delta R2 * (s-1)

80

60

40

20

0
1 16 31 46 61 76 91 106 121 136 151 166 181 196 211 226 241
Time (min)

e. The global theranostics market reached US$ 1.8 billion in 2022. It is anticipated to experience a
lucrative growth by 2030 and reach up to US$ 4.2 billion –How do you think can theranostic
nanoparticles contribute to personalized cancer medicine?