Medicinal Chemistry

CHEM 315/515
Mid-term Exam
Tuesday, October 26, 2010

Name:___Edgar Renteria___________________

Read each question carefully before answering. Be certain you understand everything the question is
requesting. Do the easy questions first. If questions appear confusing or exceedingly complex, then you may
need to rethink the question. Keep in mind the intended examination topics.
In medicinal chemistry, hand-drawn pictures convey specific information. Be sure the drawing you have made
conveys the essential information required to answer the question. Make certain that three-dimensional pictures
display the correct atom arrangements. Don't forget to include formal charges when appropriate.
You may use scrap paper to work out problems before entering your final answer on the exam sheets. In
addition, feel free to use the back side of the exam sheets for scrap. If necessary, you may enter exam answers
on the back side of the exam sheets, however you must clearly indicate which problems are located on the back
of the exam pages.
Undergraduate students answer 8 of 11 questions. Graduate students need to answer 10 of 11.

1.Identify the following biological structures as an amino acid, carbohydrate, nucleic acid, or phospholipid.
In addition, select two and give a more precise structural name, e.g. guanine or aspartic acid. (10 pts.)
NH 2
N

CH

HO

OH

OH

CH 2

O
H

H 2N

H
H

NH

-L-amino acid (histidine)

nucleic acid (adenosine)

H O

HO
HO

OH
H
OH
OH

carbohydrate (-D-glucose)

O
P
O
O
O

O
O

phospholipid (phosphatidylcholine)

2. Shown below is the X-ray structure of Merck's drug indinavir (crixivan) fitting in the active site of a protease
enzyme. The dashed lines represent interactions between the enzyme and the drug, and the curved arcs represent
pockets in the enzyme. Answer the following questions based on your understanding of this drug, related
protease drugs and their mode of action. (10 pts.)
hydrophobic
interaction
Asp25'
Asp25
O
S1

S3 subsite
hydrophobic
interaction

O
O
H-B
H
H
O
N

H-bonding (HB)
H

HN

H N

N
HN
Arg8

H
S2

Ile50

H
N

H-B
H
H
N

Gly27

S1'

H
N Asp29

H
O
H-B

O
hydrophobic
interaction

H
S2'

H
N
Ile50'

flap

hydrophobic
interaction

a) Identify all the hydrogen bonding interactions by writing 'H-B' next to them. Circle the H-bond acceptor in all
the H-bonds.
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b) What is the approximate binding energy of a hydrogen bond? A range is an acceptable answer.
10-40 kJ/mol (3-10 kcal/mol)
c) Identify the hydrophobic interactions between indinavir and the enzyme by writing 'hydrophobic interaction'
next to these contacts.
d) The pockets of the protease enzyme are occupied by several groups from indinavir. Identify these pockets by
writing the proper designation, S1, S1', etc., next to the correct pocket.
3. Indinavir represents a class of protease inhibitors that were designed to achieve their potency through a
particular process. Other examples of protease inhibitors include ritonavir and nelfinavir. (10 pts.)

a) What is the mechanism by which these protease inhibitors block HIV protease? Be as specific as possible.
These three drugs are all transition state inhibitors; that is, they mimic a transition state or intermediate in the
catalytic reaction of HIV protease. As such, they are also reversible, competitive inhibitors of the enzyme.

b) Explain why this mechanism can be so powerful in generating enzyme inhibitors.

Enzymes generate their catalytic benefits by lowering the energy of transition states and tetrahedral
intermediates in a reaction path thereby providing easier access to the products. This is primarily accomplished
by creating an environment around a particular substrate that serves to stabilize the high energy transition state
or intermediate. Since the enzyme has evolved to bind and have strong affinity for this transition
state/intermediate, the enzyme will also likely have strong affinity for a stable mimic of this transition
state/intermediate. A transition state/intermediate mimic can therefore be a quite potent inhibitor of the
enzyme.

4. Provide the curved electron flow arrows and intermediate structures for the mechanism of HIV protease. (10
pts.)
Asp25

Asp25'

HOH
O

R1

Asp25

OH

Asp25'

OH

O O
H

H
O

R1 O

Asp25

OH

N
H

R 1'

Asp25'

R1

N
H

R 1'

H
R1 '

Asp25

Asp25'

OH
R1

O O
O

H
O

H
N
H
R1 '

5. The structure of the antibiotic penicillin G is shown below. Answer the following questions based on our
discussion of penicillin. Briefly describe how penicillin exerts its antibiotic action. (10 pts.)
H
N

a) How does penicillin act as an antibiotic, i.e. what

bacterial process is undermined?

H
S
N

Penicillin inhibits bacterial wall synthesis, thereby

rendering the bacteria incapable of forming a
protective barrier to the outside world.

OH

penicillin G

b) Show the basic steps in the reaction of penicillin with transpeptidase, a serine protease.

H
N
O

H
S

O
H

N
O

OH

OH

Ser
(Ser of transpeptidase enzyme)

B:

H
N

NH H

O
N

O
O

O
Ser

O
H

OH

Ser

N
H

OH
O

B
enzyme Ser stuck with penicillin covalently
bound

c) What type of enzyme inhibition is represented by this reaction of penicillin with transpeptidase?
This process represents irreversible inhibition of the enzyme, transpeptidase.

d) What is the key reactive functionality in penicillin and why is it so reactive?

The beta-lactam ring (four member ring) is essential to the reactivity of penicillin as shown in the previous
mechanism. As a four member ring with an sp2 carbon, it has considerable bond angle strain.

e) What does penicillin mimic that allows it to react with transpeptidase?

Penicillin mimics two amino acids ,D-alaninyl-D-alanine, which are found in the natural substrate.

6. In the Billion-Dollar Molecule, Joshua Boger leaves Merck to revolutionize drug discovery. In particular, he
wants to transform the way drugs are designed. What is this 'new' type of drug design or development process
called? What happens in this process and why is this so different from previous drug design/development work
in medicinal chemistry? (10 pts.)
Josh Boger wants to use structure-based rational drug design. Fundamental to his approach is to have structural
information about the target, an enzyme or receptor. Usually this is accomplished by getting an x-ray crystal
structure of the target which allows the medicinal chemist to design molecules to fit in the active site of the
target. More traditional medicinal chemistry work simply modified the natural substrate or a lead compound and
studied the structure-activity relationships of the analogs until the desired properties were optimized.

7. During the first half of the semester, we discussed prodrugs on several occasions. The three drugs shown
below were all examples of prodrugs. (10 pts.)
a) For two of the three, identify the process that occurs to activate the drug and show the actual bioactive agent.
prontosil
H2 N

N
N
NH2

O
S NH 2

in vivo
metabolic
reduction

H2 N

NH 2
NH2

H2 N

O
S NH 2

O
sulfanamide, active antibacerial agent

enalapril

esterase
H 3CH 2CO
O

N
H

N
O

HO
OH

N
H

N
O

OH

5-fluorouracil (note: this is a long process, an abbreviated description and the final sturcture is all that is
necessary)
O
O
F

HN
O

N
H

HN

ribose ring added, ribose ring

reduced and phosphorylation and
dephosphorylation occurs

O
O P O
O

O
O

H
H
OH H

b) Two of the three drugs shown (or their bioactive derivative) are termed anti-metabolites. Choose one of these
two drugs and describe what makes it an anti-metabolite and how this action creates a therapeutic effect.
Prontosil becomes a sulfanamide as shown above and this agent competes with the metabolite paraaminobenzoic acid in the bacterial synthesis of folic acid, an essential process for bacterial growth. More
specifically, the sulfanamide is a competitive inhibitor of dihydropteroate synthetase in bacteria and therefore
acts as an antibiotic.
5-Fluorouracil (5-FU) is also an anti-metabolite as it mimics the metabolite uracil and blocks the synthesis of
thymidine, which is necessary for DNA synthesis. 5-FU is actually an irreversible inhibitor of the enzyme
thymidylate synthetase. With thymidine synthesis blocked or slowed, DNA can't be synthesized as rapidly and
this slows the growth of cancer cells.

8. A recent article in the Journal of Medicinal Chemistry (ASAP, Oct. 22, 2010) reported a study of B and C
(below) as potential anti-virals. You will recognize that both are a close structural analog of a well-known and
important biological molecule, compound A. Analyze the different physicochemical properties of these
molecules according to the criteria below. (10 pts.)

NH 2

NH 2

CH 3

N
N
HO

HO

OH

H
OH

O
H

H
OH OH

HO

O
H

H
OH OH

a) Rank the compounds shown by lipophilicity.

most lipophilic ____C___ > ___B____ > ____A____ least lipophilic
b) Rank the electronic nature of the bicyclic aromatic ring (consider rings as a whole, not individually).
most electron rich ____B___ > ___C____ > ____A____ least electron rich
c) The substitutions of atoms in A for different atoms in B and C represent an example of what kind of drug
design replacement strategy?
Isosteric functional group replacement
9. a) Predict three possible metabolites of methylphenidate (Ritalin), the most commonly prescribed treatment
for attention deficit hyperactivity disorder. At least one of the three must be a Phase I and at least one must be
Phase II. You may show a Phase II step that occurs after one of your Phase I metabolic reactions. Each
metabolic reaction should be titled with the type of reaction and the Phase (I or II). Reactions catalyzed by
cytochrome P-450 should be noted with a CYP designation. (10 pts.)

N-sulf onation
(Phase II)

OCH3

H
N
O
S O
O
OH

esterase (Phase I)
H

OCH3
H
NH O
methylphenidate

N-oxidation
(CYP, Phase I)

HO
HO

H
NH O

H
alkene oxidation
(CYP, Phase I)

N-glucuronidation
(Phase II)
alkane oxidation
(CYP, Phase I)
HO2 C

OCH3
H
O

OH

N-dealkylation
(CYP, Phase I)

O
N
OH
H
O

H
H

OCH3

OCH 3

H
NH 2 O

NH OH O
O

OCH3

H
NH O

OCH3

b) Take one of the metabolic products that you propose and propose an analogue of methylphenidate that would
block this metabolic product.
OH

F
blocked by
steric hindrance

blocked by
f luorination
H
H
NH O

OCH 3

OCH 3

H
NH O

H
NH O

blocked by NOCH 3 methylation

H
NH O

OCH 3

H
N
O
CH 3

N
O
O
S
O
OH

10. Multiple choice. Circle the one best answer for each question. (10 pts.)
a) Which of the following statements best describes a competitive enzyme inhibitor?
(i) A drug that binds to an active site and undergoes a reaction.
(ii) A drug that binds to an active site and inhibits the enzyme, but which is displaced by increasing the
concentration of substrate.
(iii) A drug that binds to an active site and inhibits the enzyme, but which is not displaced by increasing the
concentration of substrate.
(iv) A drug that binds to a different binding site from the active site and affects the activity of the enzyme.
b) Which of the following descriptions best identifies an allosteric inhibitor?
(i) A drug that binds to an active site and undergoes a reaction.
(ii) A drug that binds to an active site and inhibits the enzyme, but which is displaced by increasing the
concentration of substrate.
(iii) A drug that binds to an active site and inhibits the enzyme, but which is not displaced by increasing the
concentration of substrate.
(iv) A drug that binds to a different binding site from the active site and affects the activity of the enzyme.
c) Which of the following is not a common source for discovery of a drug lead?
(i) pharmaceutical company compound libraries
(ii) pharmacophores found through enzyme co-factor screening
(iii) natural product sources such as soil samples or mold growths
(iv) bioactive metabolites identified through animal or clinical studies
d) Which is the most common correct goal in Phase 2 of clinical trials?
(i) determine the safety of a new drug on healthy individuals
(ii) test the bioavailability of the drug in healthy people
(iii) prove the efficacy and reconfirm the safety of the drug in sick patients
(iv) expand the study to a much larger set of sick patients to confirm efficacy and safety on a larger population
of people
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11. Choose one person in the Billion-Dollar Molecule and briefly describe one positive character trait and one
negative character trait. (10 pts.)
Joshua Boger is incredibly driven and supremely confident of his ability to succeed which allows him to
accomplish great things like completing the Chugai deal. However, he is also blinded by his confidence to
problems within Vertex's operations. For example, he loses the confidence of his employees on several
occasions when they feel he is failing to direct scientific operations in a prudent manner and he is taking foolish
risks in proposing extraordinary goals for drug development in an effort to sell the company's potential to
investors.
Stuart Schreiber is passionately focused on doing great science and sharing his results with the rest of the
scientific community, but he ignores intellectual property issues that are essential to proprietary drug
development. This occurs despite his eagerness to foster entrepreneurial activity that is directly connected with
his own research.
Tom Starzl is thoroughly devoted to making his science work to the benefit of organ transplant patients. His
passion for his work is so great that at times he neglects his own health. Nevertheless, he also becomes so
obsessed with success that he engages in unethical experimental work by using foreigners as transplant patients
in highly risky operations.