PHAY0020
UCL SCHOOL OF PHARMACY
MSc Drug Discovery and Development
MSc Drug Discovery and Pharma Management
EXAMINATION
PHAY0020
THE PROCESS OF DRUG DISCOVERY (TPODD 1)
May 2020
TIME ALLOWED: 2 Hours
Answer TWO (2) of the FOUR (4) questions.
Use a separate answer book for each question you select.
Each question has the same value.
You are advised to spend no more than 60 minutes on each question.
The marks distribution is shown clearly for each section of the question. Answer all
parts of each of the individual questions you select.
Notes are not permitted in this examination.
Dictionaries are not permitted in this examination.
Calculators may be used in this examination.
Do not turn over until you are told to do so by the invigilator.
Do not take this question paper out of the examinations room.
TURN OVER
PHAY0020
2
1. Using 5HT2 receptor agonists as examples, discuss the key factors involved in
the design and evaluation of CNS drugs. (100% of marks)
2. Answer ALL parts of the question
You are about to collaborate with a medicinal chemist on a structure-based drug
discovery research programme involving the characterisation and design of a
new small molecule inhibitor targeting a known receptor protein.
a) Briefly describe the approaches you might undertake to characterise and
understand a target receptor binding pocket on a protein to aid in the design of
a novel inhibitor. (30 % of marks)
b) Explain the different interactions and molecular forces involved in the
intermolecular interactions between a typical protein receptor and ligand, and
discuss the relative importance of each one. (30 % of marks)
c) Your collaborators provide you with new coordinates for the receptor protein
structure identifying the potential binding pocket but without a ligand bound.
Explain how you might be able to exploit this new structural data using a
computational-based docking approach to improve the design and binding
affinity of a lead small molecule compound identified through an inhibition
assay. (40 % of marks)
3. Answer ALL parts of the question:
A research laboratory has created a knockout mouse for protein X and
discovered that the phenotype displays dramatically reduced food intake and
reduced body mass.
a) Explain the molecular techniques the research team are likely to have used to
create their knockout mouse model. (50 % of marks)
b) The team are keen to know whether naturally occurring polymorphisms or
mutations in the gene for protein X result in clinical manifestations in humans.
Explain how linkage analysis or association studies by clinical researchers
might provide evidence for this (25 % of marks)
c) Describe the molecular mechanisms involved in ONE example where a gene
mutation results in a clinically identifiable disease. (25 % of marks)
TURN OVER
PHAY0020
3
4. Answer ALL parts of the question:
A small pharma company believes that it has identified the pharmacophore that
inhibits growth factor stimulated mitosis by preventing transcription factor
binding to DNA. It intends to use this pharmacophore to synthesise a chemical
library of lead compounds.
a) Explain the difference between the terms pharmacophore and lead compound.
How might the pharmacophore have been identified (25 % of marks)
b) Describe and explain ONE method of combinatorial chemical synthesis that
might be used to make the library. Discuss the advantages and disadvantages
of the process you choose. (35 % of marks)
c) The company has access to pure samples of the transcription factor target and
have experience in cell culture experiments. Describe and explain ONE in vitro
biochemical bioassay and ONE cell-based bioassay that the pharma company
could use in the high-throughput screening of their chemical library.
(40 % of marks)
END OF PAPER
