Problem Set 5
1. Draw
two plots (A and B together, then A and C together) that show how an
enzyme-catalyzed reaction rate (velocity) varies with substrate concentration.
For Case A, there is no inhibitor present. For Case B, there is a competitive
inhibitor present. For Case C, there is a noncompetitive inhibitor present. Be
sure to show the KM and the Vmax
for each of the three cases on the two plots. Clearly describe the difference
between competitive and noncompetitive inhibitors.
2. For
the three cases in the previous problem, draw two Lineweaver-Burk
plots and clearly label each of these.
3. For
an enzyme catalyzed reaction, calculate the fraction of enzyme sites filled
with substrate when the substrate concentration is 2/3 of the Michaelis constant (KM).
4. Examination
of a receptor interaction study of three drugs undergoing clinical trials
revealed affinity constants Ki’s of
40 nM, 2 mM,
and 900 pM for Drugs A, B, and C respectively. Drug A was found to have greatest efficacy, while Drug B was
found to have the lowest efficacy.
a. Draw a dose-response plot that illustrates the
curves for drugs A, B and C.
b. Clearly
define what is specifically meant by a drug’s efficacy and potency
c. Describe
the relative potency and efficacy for drugs A, B, and C; clearly support your
answer.
d. Compare
the relative affinities of the three drugs for the receptor binding site and
clearly support your answer.
5. The
side chain in cysteine has a pKa
of 8.00. For a pH of 7.4, draw the complete
Lewis structures of the two most concentrated forms of cysteine. Show which form is present at a greater
concentration. Calculate the percentage
of cysteine that is in the most concentrated form at
this pH.
6. Dopamine
has a pKa of 10.6; draw the Lewis structure
of the most prevalent form of dopamine at physiological pH. Comment on the
tendency of this form to cross the blood-brain barrier.
7. Salmeterol is a b2 adrenoreceptor
agonist that is a bronchodilator with a slow onset and a long duration of
action due to its log P value of 3.88.
Albuterol
has a log P value of 0.66 and is a fast acting b2 adrenoreceptor
agonist that is a bronchodilator.
a. Use
thermodynamics and molecular structures to clearly explain the basis for the
difference in P values for these two substances.
b. If
3 mmoles of albuterol were
added to a mixture of 25 mL of water and 50 mL of 1-octanol, calculate the mmoles
of albuterol that would partition to the 1-octanol
phase.
c. Salmeterol has a b2 adrenoreceptor
affinity constant Ki of 53 nM and an efficacy of 65%; albuterol
has b2 adrenoreceptor affinity constant Ki
of 2.5 mM and an efficacy
of 85%. Formoterol has b2 adrenoreceptor
affinity constant Ki of 75 nM and an efficacy of 100%.
Use the same graph to plot the dose-response curves for these three b2 adrenoreceptor
agonists.