Final Flashcards

1
Q

By what mechanism do DNA polymerase inhibitors such as aciclovir work?

A

DNA polymerization requires a hydroxyl which acyclovir lacks, thus polymerization is halted after the addition of aciclovir triphosphate.

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2
Q

What makes aciclovir more specific to viral-infected cells?

A

The first phosphate is added by viral thymidine kinase, which aciclovir has much greater selectivity for.

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3
Q

What are the main targets in the HIV life cycle

A

fusion/entry; reverse transcriptase; HIV protease; integrase

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4
Q

How do nucleoside RT inhibitors work?

A

Chain termination at the step of building DNA onto the RNA template

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5
Q

What is the major difference in the mechanism for non-nucleoside RT inhibitors vs. NRTIs

A

NNRTIs bind allosterically to reverse transcriptase to change conformation to inactive

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6
Q

Explain fxn of HIV protease

A

Cleaves polyproteins into fxnl mature proteins

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7
Q

What design principle were important in the first HIV protease inhibitors

A

Transition state isotere of the peptide bond btwn phenylalanine and proline; the binding sites of the other residues in the viral polypeptide POL

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8
Q

Why do symmetric protease inhibitors show selectivity to viral proteases

A

Mammalian proteases are not symmetric

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9
Q

How do entry/fusion inhibitors work

A

Can bind to gp120 or gp41; block CD4 or CCR5

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10
Q

How do integrase inhibitors work?

A

Bind Mg 2+ ions in the active site to block the binding of DNA

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11
Q

What is neuraminidase and how is it important to the influenza life cycle?

A

Cleaves sialic acid to degrade mucus layer and allow virus to reach surface epithelial cells

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12
Q

What design principles are important for NA inhibitors?

A

The transition state of the carboxylate ion being in the equatorial position interacting arginine residues

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13
Q

How do sulfonamides work against bacteria?

A

Inhibits the production of tetrahydrofolate, which ultimately inhibits purine synthesis (inhibits dihydropteroate synthetase)

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14
Q

What enzyme does penicillin inhibit and what is the general mechanism?

A

Transpeptidase, responsible for crosslinking bacterial cell wall; serine residue hydrolyzes the lactam ring which binds penicillin to active site and blocks bacterial peptide and water from entering active site

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15
Q

What is the significance of the double ring system in penicillin?

A

The bond angles are restricted, thus there is no resonance between the nitrogen and carbonyl, making the amide bond sensitive to hydrolysis/cleavage

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16
Q

Why did later analogues of penicillin include an electron-withdrawing group?

A

To help prevent auto-hydrolysis of the β-lactam ring

17
Q

How do β-lactamases cause resistance to penicillin?

A

They hydrolyze the β-lactam ring but are not inhibited by them, thus can inactivate the drug with a very high catalytic efficiency

18
Q

What design element was added to combat β-lactamases?

A

Steric shields that can block entry into the active site of the β-lactamases but still allow access to transpeptidase

19
Q

How do cephalosporins work against bacteria?

A

Similar mechanism to penicillin, cleavage of the β-lactam ring

20
Q

What is the main difference between cephalosporins and penicillin?

A

Cephalosporins have much lower activity (1/1000)

21
Q

What is another way to target penicillin-resistant bacteria?

A

Specific inhibitors of β- lactamases; modifying scaffold

22
Q

Explain generally how vancomycin works against bacteria.

A

The peptide chain of the bacterial cell wall hydrogen bonds with the hexapeptide of vancomycin, and vancomycin blocks access to key enzymes

23
Q

What are the other three main routes for antibacterial agents (aside from antimetabolites and inhibition of cell wall synthesis)?

A

cell membrane disruption, translation inhibition, inhibition of transcription/replication

24
Q

Explain the general mechanism for alkylating agents to crosslink two guanines.

A

A reactive carbon covalently binds to the nitrogens on guanines, a symmetric molecule
so can happen twice

25
Q

5 fluorouracil is considered an anti-metabolite, what is the significance of the fluorine at position X?

A

Uridine has a hydrogen at the X position which allows for the full reaction to add the methyl group for thymidine. Having a fluoro substituent blocks the rest of the synthesis

26
Q

What is the general principle behind hormone therapy for cancer?

A

Estrogens inhibit production of luteinizing hormone and decrease synthesis of testosterone; Androgens can suppress levels of LH and decrease estrogen

27
Q

In trying to block the production of testosterone, why would agonists be used?

A

Sensitization: overstimulation of receptors will lead to decrease production of said receptor over time.

28
Q

What is a key design principle for kinase inhibitors?

A

Utilizing the conserved residues that interact with ATP in the binding site

29
Q

What other features in the ATP-binding site of kinases can be utilized for kinase inhibitors?

A

Hydrophobic pocket, ribose pocket, and cleB

30
Q

What are possible reasons for subsequent generations of kinase inhibitors?

A

Mutations that cause resistance, improving PK/PD profile

31
Q

In the picture below, II was the lead compound for I. What is the significance of the F and Cl?

A

Prevent metabolic inactivation

32
Q

What is the significance of targeting structural proteins (i.e. tubulin) for cancer therapies?

A

Tubulin polymerization and depolymerization is necessary during cell division, thus disrupting this process helps halt the growth of tumors

33
Q

Matrix metalloproteinase is a good target for cancer therapy, what are the two key design principles for inhibitors?

A

transition state isostere (peptide bond between glycine and isoleucine) and coordination with a Zn2+ ion