1 - GUL

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Individual assignment
Drug development 7.5 ECTS, KMG045 (Chalmers)/ BIO523 (GU) fall term 2013
Submit your answers (as attached Word, pdf, or text files) by E-mail to
[email protected] no later than Friday Dec. 20
Treat one of the following topics, using no more than 2000 words (excluding
literature references). All literature is allowed as an aid. The essay is then graded on
a scale from 0 to 10. The points are added to the points of the regular final exam.
There is not one, but several possible “correct” answers for each topic. The more
appropriate and realistic answer (still respecting the upper limit of 2000 words), the
higher the grade.
Each essay must be an original document produced by the student, and each
document will be automatically scanned by “Urkund” in order to reveal cases of
plagiarism. It is allowed to co-operate between you in discussions about a literature
topic, but each essay still has to be original and unique.
1. Proteins are generally the functional units of cells and are therefore the most logical
drug targets. A majority of proteins (some claim that almost all) work in complex
with other proteins as heteromeric complexes where both components are equally
important for function, i.e. inhibition of either one of the proteins in the complex
results in drastic effects on the activity of the whole complex. Thus, in cases where
one protein has been identified as an important target to treat a disease, there is great
interest to find other proteins that physically link to the first protein.
There are various techniques to screen for proteins that physically interact with an
important disease protein thereby identifying potentially new drug target. Discuss
various means to screen for these new targets, in particular to human GPCRs. GPCRs
are the most common class of drug target and therefore of great medical importance.
In particular, consider using other organisms/systems as test-bed for the screens and
compare those procedures to methods where one can screen for physical interactions
directly in the human systems. What are the pros and cons in time, money and
outcome?
2. Small molecules (fragments) binding to a protein, are considered attractive starting
points for findings leads in a drug hunting campaign. In order to develop the
fragments hits into useful leads, several methods have been described (fragment
linking, merging, growing, etc). Describe two such methods, using an example from
literature for each one. Discuss the reasons the authors had for selecting the particular
strategy for each case, and discuss, and possibly explain, the changes in chemical
structure that caused the improvement, in affinity or selectivity, obtained in the
process.
3. Designing drugs with activity against eukaryotic parasites (Trypanosoma,
Leishmania, Plasmodium etc.) presents a formidable challenge. The main reason is
that the gene products of these organisms is so similar to our own homologs that it is
difficult to avoid side activity against our own cells; in other words there is a great
problem of selectivity. Assuming you have access to small molecules with some
selectivity against a parasite (i.e. they kill off the parasites more efficiently than our
own cells at a given concentration), but the selectivity needs to be improved.
Furthermore, the molecular target of these molecules is not known. Discuss how you
can use yeast as a tool to identify the target protein (or at least the targeted pathway)
of such a compound. Assuming this first step was successful, discuss how you can use
yeast in a second step to also improve the selectivity (its inhibitory effect vs. the
parasite protein homolog over that vs. the human protein homolog) of the compound
by screening among related molecules.
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