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Mid-term Exercises
E8130 – Medicinal Chemistry
SOLUTIONS
1)
Name three intramolecular attractive forces that contribute to a productive
drug-target interaction and provide for each of them one typical functional
group and/or specific amino acid that can engage in this type of binding.
a) van-der Waals interaction
typical functional group: phenylalanine
(also correct: Val, Leu, Trp, Ile,...
b) H-bonding interaction
typical functional group: peptidic amide bond
(also correct: Ser, Thr, Tyr,...)
c) halogen-bonding
typical functional group: histidine
another possibility:
d) ionic bonding
typical functional group: arginine
(also correct: Lys, Asp, Glu)
2)
The first pass effect plays a crucial role in the activation and/or deactivation
of drugs. Briefly describe the general features of the first pass and explain
its particular function in the activation of the following two prodrugs
(involved enzymes, structure of the generated active form).
O
O
O
O
Me2N
Cl
clofibrate
(LDL lowering agent)
tamoxifen
(anti-estrogen)
(the important terms are marked bold)
The first pass describes the effect, that orally administered drugs are absorbed
in the gastrointestinal system (stomach and/or small intestines) from where they
pass the liver via the portal vein before reaching the systemic blood stream and
the target organs. The liver provides a very effective enzymatic machinery with
highly active hydrolases, oxygenases and reductases. Drugs are thereby
structurally altered which can lead to deactivation, activation or the formation of
toxic metabolites.
The prodrug concept exploits the first pass by using molecules that do not act as
drug, but that can be activated by cleavage of labile groups or oxidation to
yield the bioactive compound. Prodrugs often show better membrane
permeability and are hence easier absorbed.
Prodrug concept in clofibrate: ester hydrolysis
O
O
O
esterase
O
O
Cl
OH
Cl
Prodrug concept in tamoxifen: hydroxylation
O
Me2N
cytochrome
P450
O
Me2N
OH
3)
Indicate one potential pharmaceutical application for each of the following
drug molecules. What are the target proteins of the drugs (if applicable) and
which physiological function is modulated by the interaction.
a)
b)
OH OH
O
COOH
N
OH
O
F
OH
c)
H
H
H
H
O
a)
application: cholesterol-lowering agent, prevention of stroke or cardiac arrest
(one is enough)
target protein: HMG-CoA reductase
modulated function: biosynthesis of cholesterol (also ok: mevalonate, terpene bio
synthesis)
b)
application: pain killer, antiinflammatory agent, anti-coagulant (one is enough)
target: cyclooxygenase
modulated function: prostaglandin/thromboxane biosynthesis
c)
application: against growth failure diseases, bone marrow stimulation, muscle
growth (one is enough)
target: androgen receptor
modulated function: signaling cascade to develop male sexual characteristics,
...to support gain of bone structure and sceletal muscles
4)
Briefly explain the function of low-density lipoproteins and its involvement in
plaque formation.
(the important terms are marked bold)
Low-density lipoprotein (LDL) is a transport vesicle for lipophilic compounds
such as triglycerides and cholesterol. It transports cholesterol from the liver to
the target tissues and serves as reservoir for cholesterol in the blood.
LDL is instable and readily associates with the arterial walls. Accumulation of
LDL leads to the formation of foam cells/fatty streak which eventually results in
thrombotic clot formation.