Assignment-4

1. Valinomycin is an antibiotic which is able to transport ions across cell membranes and disrupt
the ionic balance of the cell. Find out the structure of valinomycin and explain why it is able to
carry out this task.
2. Identify the intermolecular/intramolecular interactions that are possible for the side chains
of the following amino acids; serine, phenylalanine, glycine, lysine, aspartic acid, and aspartate.
3. The chains of several cell membrane-bound proteins wind back and forth through the cell
membrane, such that some parts of the protein structure are extracellular, some parts are
intracellular, and some parts lie within the cell membrane. How might the primary structure of
a protein help in distinguishing the portions of the protein embedded within the cell membrane
from those that are not?
4. The tertiary structure of many enzymes is significantly altered by the phosphorylation of
serine, threonine, or tyrosine residues. Identify the functional groups that are involved in these
phosphorylations and suggest why phosphorylation affects tertiary structure.
5. Enzymes can be used in organic synthesis. For example, the reduction of an aldehyde is
carried out using aldehyde dehydrogenase. Unfortunately, this reaction requires the use of the
cofactor NADH, which is expensive and is used up in the reaction. If ethanol is added to the
reaction, only catalytic amounts of cofactor are required. Why?
6. The ester bond of acetylcholine is hydrolyzed by acetylcholinesterase. Suggest a mechanism
by which the enzyme catalyzes this reaction. Suggest how binding interactions might make
acetylcholine more susceptible to hydrolysis.
7. Consider the structures of the neurotransmitters shown in Fig. 4.3 and suggest what type of
binding interactions could be involved in binding them to a receptor binding site. Identify
possible amino acids in the binding site which could take part in each of these binding
interactions.
8. Suggest why the transmembrane regions of many membrane-bound proteins are α-helices.
9. The enzyme cAMP phosphodiesterase hydrolyses cAMP to AMP. What effect would an
inhibitor of this enzyme have on glucose-1-phosphate production
10. An enzyme was produced by genetic engineering where several of the serine residues were
replaced by glutamate residues. The mutated enzyme was permanently active, whereas the
natural enzyme was only active in the presence of a serine–threonine protein kinase. Give an
explanation.
11. Suggest why tyrosine kinases phosphorylate tyrosine residues in protein substrates, but not
serine or threonine residues.
12. Proflavine is a topical antibacterial agent which intercalates bacterial DNA and was used to
treat wounded soldiers in the Far East during World War II. What role (if any) is played by the
tricyclic ring and the primary amino groups? The drug cannot be used systemically. Suggest why
this is the case.

13. The following compounds are antiviral drugs that mimic natural nucleosides. What
nucleosides do they mimic?

14. It is known that the amino acid at position 523 of the cyclooxygenase enzyme is part of the
active site. In the isoenzyme COX-1, this amino acid is isoleucine, whereas in COX-2, it is valine.
Suggest how such information could be used in the design of drugs that selectively inhibit COX-
2.
15. Neostigmine is an inhibitor of acetylcholinesterase. The enzyme attempts to catalyze the
same reaction on neostigmine as it does with acetylcholine. However, a stable intermediate is
formed which prevents completion of the process and which results in a molecule being
covalently linked to the active site. Identify the stable intermediate and explain why it is stable.
16. Structure I is an agonist which binds to the cholinergic receptor and mimics the action of the
natural ligand acetylcholine. Structure II, however, shows no activity and does not bind to the
receptor. Suggest why this might be the case.

17. If you were asked design drugs that acted as selective antagonists of the dopamine
receptor, what structures might you consider synthesizing?
18. The following structure is an important antiviral agent. Suggest what mode of action it may
have and the mechanism by which it works.

19. The p K a of histamine is 5.74. What is the ratio of ionized to un-ionized histamine (a) at pH
5.74 (b) at pH 7.4?
20. A drug has a half-life of 4 hours. How much of the drug remains after 24 hours?
21. Salicylic acid is absorbed more effectively from the stomach than from the intestines,
whereas quinine is absorbed more effectively from the intestines than from the stomach.
Explain these observations.
22. What is meant by target specificity and selectivity? Why is it important?
23. What are the advantages and disadvantages of natural products as lead compounds?
24. Fungi have been a richer source of antibacterial agents than bacteria. Suggest why this
might be so.
25. Scuba divers are advised not to touch coral. Why do you think this might be? Why might it
be of interest to medicinal chemists?
26. You are employed as a medicinal chemist and have been asked to initiate a research
programme aimed at finding a drug which will prevent a novel tyrosine kinase receptor from
functioning. There are no known lead compounds that have this property. What approaches can
you make to establish a lead compound?
27. A lead compound containing a methyl ester was hydrolyzed to give a carboxylic acid. An in
vivo bioassay suggested that the ester was active and the acid was inactive. However, an in
vitro bioassay suggested that the ester was inactive and the acid was active. Explain these
contradictory results.
28. A lead compound contains an aromatic ring. The following structures were made as
analogues. Structures I and II were similar in activity to the lead compound, whereas structure
III showed a marked increase in activity. Explain these results and describe the strategies
involved.

29. Suggest why the oxygen atoms in the following structures are poor hydrogen bond acceptors.

30. Compare the ability of the nitrogen atoms in the following structures to act as hydrogen
bond acceptors.

31. Acetylcholine is a neurotransmitter that is susceptible to chemical and enzymatic hydrolysis.

Suggest strategies that could be used to stabilize the ester group of acetylcholine, and show the
sort of analogues which might have better stability.
32. The oral bioavailability of the antiviral drug aciclovir is only 15–30%. Suggest why this may
be the case and how one might increase the bioavailability of this drug.

33. A pharmaceutical laboratory wishes to synthesize all the possible dipeptides containing the
amino acids tyrosine, lysine, phenylalanine, and leucine. Identify the number of possible
dipeptides and explain how the laboratory would carry this out using combinatorial techniques.
What particular precautions have to be taken with the amino acids tyrosine and lysine in the
above synthesis?
34. A fine balance of binding interactions is required of a neurotransmitter. What do you think
is meant by this and what consequences does it have for drug design?
35. Suggest how the binding interactions holding acetylcholine to the active site of
acetylcholinesterase might aid in the hydrolysis of acetylcholine.
36. Morphine is an example of a plant alkaloid. Alkaloids tend to be secondary metabolites that
are not crucial to a plant's growth and are produced when the plant is mature. If that is the
case, what role do you think these compounds have in plants, if any?
37. Morphine is the active principle of opium. What is meant by an active principle?
38. The acidic contents of the stomach encourage the digestion of food and the destruction of
cells. Why are the cells lining the stomach not digested in that case?
39. What are the Lipinski‘s rules of five and what do they stand for?
40. What are the advantages of using mixtures of compounds in the biological screening? What
are the disadvantages?
41. What are the advantages of using solid phase chemistry?
42. For which type of molecules is it advantageous to use solid phase chemistry?
43. What are the advantages of a split-mixed approach over a parallel synthesis approach and
for which types of molecules will you apply this technology? Please discuss.
44. Parallel synthesis facilitates the synthesis of libraries with diverse chemical structures that
can be screened for potential biological activity. Justify