PHAY0029 MODERN ASPECTS OF DRUG DISCOVERY 2022
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PHAY0029
MODERN ASPECTS OF DRUG DISCOVERY (MADD)
January 2022
Section A
DRUG DISCOVERY CASE STUDIES
1. Answer BOTH parts of the question:
“Adrenaline was the lead compound for the discovery and development of drugs such as atenolol”
a) With reference to the structures of compounds 1 & 2 illustrated below, discuss and explain this statement giving evidence to support your views. (70% of marks)
Beta blockers e.g. Atenolol (2) and H2 antagonists e.g. Cimetidine (4) share common features in their pathways of discovery and development and in their mechanism of pharmacological action.
b) Describe and explain some of these similarities to illustrate the process of rational drug discovery. (30% of marks)
2. A pharmaceutical company carried out an analysis of a protein-protein interaction (PPI) that plays a role in cancer. After sequencing, isolating and purifying the proteins involved, structural studies (X-ray crystallography) showed that the PPI interface involves an α-helical motif from one protein interacting with a groove on the surface of its partner. The ‘hot spot’ region of the helical motif involved three residues (Ile, Trp and Tyr) that occupy the groove.
Describe how you might develop a protein-protein interaction inhibitor that occupies the binding pocket. In your answer (i) explain why the hot spot residues are important and (ii) describe TWO drug design approaches that you could adopt. What are their advantages and disadvantages? How might you test your inhibitors in a high-throughput assay? (100 % of marks)
Section B
TECHNIQUES IN DRUG DISCOVERY
3. Answer BOTH parts of the question:
The administration of paracetamol to HepG2 cells, a human hepatic cell line, can induce cytotoxic effects due to oxidative stress. This can be observed experimentally by visualizing a reduction in the levels of cellular antioxidant enzymes such as superoxide dismutase.
Studies suggest that lemon peel extract has antioxidant capacity. Therefore, you decide to test the antioxidant potential of lemon peel extract in HepG2 cells dosed with paracetamol. In an experiment you treat HepG2 cells as follows:
1. HepG2 cells with a single dose of paracetamol (oxidative stress model)
2. HepG2 cells dosed with lemon peel extract followed by a single dose of paracetamol 24 hours later
3. HepG2 cells dosed with lemon peel only
4. Untreated HepG2 cells (negative control)
Protein samples were collected from all 4 cell models described above to determine changes in protein expression of antioxidant enzymes.
a) Describe how you could use gel electrophoresis to compare the 4 different proteinsamples. In your answer, also explain how, using mass spectrometry, you could identify a protein band on the gel as superoxide dismutase given that the protein has a molecular weight of approximately 32 kDa. (70 % of marks)
b) Your laboratory has a monoclonal antibody for superoxide dismutase which only recognises the native form of the protein. How could you use this antibody to quantify the amount of superoxide dismutase present in the 4 different cellular protein extracts? (30 % of marks)
4. Answer ALL parts of the question:
A manufacturer of maximum strength ibuprofen has found a batch of substandard tablets that were contaminated by an impurity. This impurity has since been isolated and purified in order to identify issues in the synthesis of the active pharmaceutical ingredient. Preliminary analytical data of the purified impurity was acquired. You have been asked to identify the impurity based on a 1D 1H NMR spectrum and provide an initial analysis of potential problems that can occur in the manufacturing process.
a) Explain the type of information obtained from NMR spectra that could be used to conduct structural characterization. (30% of marks)
b) Suggest the structure of the identified impurity and using ALL information that can be obtained from 1D 1 H NMR spectra and the available structures shown above provide a detailed justification for your answer (60% of marks)
c) How could other types of NMR analyses confirm the structure of the identified impurity (10% of marks)
Section C
Pharmaceutical industry and new technology
5. Answer BOTH parts of the question:
a) Discuss the key drivers that have enabled growth and innovation within the pharmaceutical industry. (70 % of marks)
b) Drug pricing is constantly under scrutiny. Briefly outline the considerations taken into account when setting a drug price and give your opinion on why price gouging occurs. (30% of marks)
6. Answer BOTH parts of the question:
You are a health care professional with a good drug discovery background working in the immunology field. Part of your job requires you to answer questions from members of the public, which means you often need to adjust your vocabulary to meet their background knowledge. Recently, an MSc student reached out to you and has sent you some questions related to the diagram below:
a) How would you explain what this diagram means in the context of vaccine
strategies? In your answer, discuss using one example for each, the vaccine strategies associated with the immune responses shown in both A and B. (70 % of marks)
The same student has also asked you about the importance of breastfeeding new-born babies in terms of immunology.
b) Give your response to the question and include in your answer a discussion on why it is recommended to breastfeed small babies and until when. Discuss the timing of the first three immunisations for children in the U.K. and link this to your answer for part A. (30 % of marks)
2024-01-09