Final Flashcards
By what mechanism do DNA polymerase inhibitors such as aciclovir work?
DNA polymerization requires a hydroxyl which acyclovir lacks, thus polymerization is halted after the addition of aciclovir triphosphate.
What makes aciclovir more specific to viral-infected cells?
The first phosphate is added by viral thymidine kinase, which aciclovir has much greater selectivity for.
What are the main targets in the HIV life cycle
fusion/entry; reverse transcriptase; HIV protease; integrase
How do nucleoside RT inhibitors work?
Chain termination at the step of building DNA onto the RNA template
What is the major difference in the mechanism for non-nucleoside RT inhibitors vs. NRTIs
NNRTIs bind allosterically to reverse transcriptase to change conformation to inactive
Explain fxn of HIV protease
Cleaves polyproteins into fxnl mature proteins
What design principle were important in the first HIV protease inhibitors
Transition state isotere of the peptide bond btwn phenylalanine and proline; the binding sites of the other residues in the viral polypeptide POL
Why do symmetric protease inhibitors show selectivity to viral proteases
Mammalian proteases are not symmetric
How do entry/fusion inhibitors work
Can bind to gp120 or gp41; block CD4 or CCR5
How do integrase inhibitors work?
Bind Mg 2+ ions in the active site to block the binding of DNA
What is neuraminidase and how is it important to the influenza life cycle?
Cleaves sialic acid to degrade mucus layer and allow virus to reach surface epithelial cells
What design principles are important for NA inhibitors?
The transition state of the carboxylate ion being in the equatorial position interacting arginine residues
How do sulfonamides work against bacteria?
Inhibits the production of tetrahydrofolate, which ultimately inhibits purine synthesis (inhibits dihydropteroate synthetase)
What enzyme does penicillin inhibit and what is the general mechanism?
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
What is the significance of the double ring system in penicillin?
The bond angles are restricted, thus there is no resonance between the nitrogen and carbonyl, making the amide bond sensitive to hydrolysis/cleavage
Why did later analogues of penicillin include an electron-withdrawing group?
To help prevent auto-hydrolysis of the β-lactam ring
How do β-lactamases cause resistance to penicillin?
They hydrolyze the β-lactam ring but are not inhibited by them, thus can inactivate the drug with a very high catalytic efficiency
What design element was added to combat β-lactamases?
Steric shields that can block entry into the active site of the β-lactamases but still allow access to transpeptidase
How do cephalosporins work against bacteria?
Similar mechanism to penicillin, cleavage of the β-lactam ring
What is the main difference between cephalosporins and penicillin?
Cephalosporins have much lower activity (1/1000)
What is another way to target penicillin-resistant bacteria?
Specific inhibitors of β- lactamases; modifying scaffold
Explain generally how vancomycin works against bacteria.
The peptide chain of the bacterial cell wall hydrogen bonds with the hexapeptide of vancomycin, and vancomycin blocks access to key enzymes
What are the other three main routes for antibacterial agents (aside from antimetabolites and inhibition of cell wall synthesis)?
cell membrane disruption, translation inhibition, inhibition of transcription/replication
Explain the general mechanism for alkylating agents to crosslink two guanines.
A reactive carbon covalently binds to the nitrogens on guanines, a symmetric molecule
so can happen twice
5 fluorouracil is considered an anti-metabolite, what is the significance of the fluorine at position X?
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
What is the general principle behind hormone therapy for cancer?
Estrogens inhibit production of luteinizing hormone and decrease synthesis of testosterone; Androgens can suppress levels of LH and decrease estrogen
In trying to block the production of testosterone, why would agonists be used?
Sensitization: overstimulation of receptors will lead to decrease production of said receptor over time.
What is a key design principle for kinase inhibitors?
Utilizing the conserved residues that interact with ATP in the binding site
What other features in the ATP-binding site of kinases can be utilized for kinase inhibitors?
Hydrophobic pocket, ribose pocket, and cleB
What are possible reasons for subsequent generations of kinase inhibitors?
Mutations that cause resistance, improving PK/PD profile
In the picture below, II was the lead compound for I. What is the significance of the F and Cl?
Prevent metabolic inactivation
What is the significance of targeting structural proteins (i.e. tubulin) for cancer therapies?
Tubulin polymerization and depolymerization is necessary during cell division, thus disrupting this process helps halt the growth of tumors
Matrix metalloproteinase is a good target for cancer therapy, what are the two key design principles for inhibitors?
transition state isostere (peptide bond between glycine and isoleucine) and coordination with a Zn2+ ion
