assignment 4

Question 1

What is a classical isostere? Give an example.

Answer 1

Atoms or groups that have the same valency or similar sizes.
For example, an OH group could be replaced with any of the following isosteres: F,
NH2, CH3 (same row of periodic table) or SH (same column of periodic table)

Question 2

What is a non-classical isostere? Give an example.

Answer 2

Atoms or groups that have similar chemical or biological properties. They usually
differ in electronics or sterics, but behave in similar ways in biological systems.
For example, a carboxylic acid could be replaced by acidic groups with similar pKa’s.

Question 3

Why was Salvarsan 606 not a commercial success?

Answer 3

It was not very drug like. Because of insolubility and high toxicity, it was very inconvenient for the patient.

Question 4

Sulfanilamide was the first commercially successful antibiotic. How does sulfanilamide inhibit bacteria cell growth? What mode of inhibition does it employ? Use a diagram to show how sulfanilamide is able to achieve this inhibition?

Answer 4

• Inhibits the bacterial enzyme dihydropteroate synthase, which is required to make coenzyme F. Without this coenzyme, bacteria are unable to grow.
• Competitive inhibition

Question 5

Penicillin kills bacteria by blocking cell wall synthesis. Why does the destruction of bacterial cell walls lead to bacterial death? How does penicillin prevent cell wall synthesis? How does cross-linking increase the strength of polymer molecules? What enzyme does penicillin inhibit? What peptide structure does penicillin resemble?

Answer 5

• Cell walls are needed to resist high osmotic pressure inside bacterial cells. Without an intact cell wall, the bacterial membrane bursts killing the bacteria
• Inhibits transpeptidase, the enzyme that performs the cross linking to form the cell wall structure
• Prevents molecules from sliding or moving relative to one another. The structure becomes a giant molecule.
• Transpeptidase
• D-Ala-D-Ala

Question 6

The enzyme that bacteria use for cell wall cross-linking is a serine protease. What is the role of the catalytic triad in a serine protease? What three amino acids make up the catalytic triad? What is the role of the oxyanion hole in a serine protease? Write out the general mechanism of a serine protease. Give a mechanism to show how penicillin inhibits a serine protease. Why does the enzyme “stop” once it has reacted with penicillin?

Answer 6

a) OH of the serine is a nucleophile that reacts with the amide carbonyl. The Asp and His act together to form a base that deprotonates the OH of the serine.
b) Aspartic acid, histidine, serine
c) Stabilize the negatively charged oxygen that is part of the tetrahedral intermediate involved in amide bond hydrolysis
d) notes
e) notes
f) Enzyme does not fold around the drug the same way that it folds around the cross-link precursor. After the first step, it is not in the proper conformation to perform the second step and gets “stuck” with the penicillin residue.

Question 7

What is the source of the allergy side effect from penicillin?

Answer 7

Penicillin reacts chemically with a serine protease or protein with a nucleophilic side chain. This changes the human protein into something the immune system recognizes as foreign. + picture to look at

Question 8

Would you expect the following compound to be a broad or narrow spectrum
antibiotic? Why or why not? (picture)

Answer 8

Compound is likely a broad spectrum antibiotic. NH2 group on side chain is hydrophilic

Question 9

question nine

Answer 9

look in the notes please

Question 10

question ten

Answer 10

also look in the notess:(

Question 11

Many modern bacteria have become resistant to penicillin. What does drug resistance mean? Show how bacteria use -lactamase to become resistant to penicillin. Show how penicillin can be modified to overcome this resistance. Provide a structural justification for your answer in part c

Answer 11

a) Bacteria are no longer affected by the drug.
b) picture
c) picture
d) picture

Question 12

The first penicillin discovered had a narrow therapeutic window. What is meant by the term therapeutic window? Why did the original penicillin drug show this behavior? What structural modifications can be made to penicillin to overcome this
difficulty?

Answer 12

a) The drug only affected a few bacteria types. In the case of penicillin, it was only effective against gram-positive bacteria.
b) Penicillin was unable to penetrate through the liopolysaccharide layer surrounding the cell walls of gram negative bacteria.
c) Attach hydrophilic groups to the side chain of penicillin

Question 13

Describe how prodrugs can be used to improve penicillin bioavailability. What structural element in penicillin is used for this purpose? Why are prodrugs necessary when making this structural change?

Answer 13

Increase water solubility by ensuring the molecule is charged at pH 7.4. This is often
done by attaching a removable group that blocks one of the charged sites on the
drug
a) Attachment is usually made on the carboxylic acid + picture
b) Both charges are necessary for this molecule to work. The NH3+ is important
for acid stability in the stomach, the CO2- is necessary to fit into the active site of transpeptidase. Prodrugs provide a temporary way of blocking the CO2-

Question 14

What structural feature is common to penicillins and cephalosporins? Why is this chemical structure important?

Answer 14

B-lactam. This functional group is a strong electrophile, which is required to react
with the active site OH nucleophile of transpeptidase

Question 15

Describe the mode of inhibition of vancomycin

Answer 15

Vancomycin binds tightly to D-Ala-D-Ala, which prevents transpeptidase from reacting with the tail end of the cell wall pre-cross-link chain