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CHEM 167
Medicinal Chemistry Final
| Question | Answer | |||
|---|---|---|---|---|
| What is the significance of molecular orbitals? | Tells us something about molecular reactivity | Can be calculated through quantum mechanics | Care about where electrons are | |
| What is the significance of molecular dynamics? | Used to probe structure and dynamics | Don't care where electrons are | ||
| What is High Throughput Screening (HTS)? | Actual experimental approach that tests tons of compounds to find a hit | Very rapid way of performing synthesis | ||
| What is virtual screening? | Only test top compounds that will actually be likely binders | Predicted from a computer | ||
| What are some different ways to generate lead compounds? | Take an already approved drug and modify it | De novo approach (LUDI) - link small molecules together on a computer | Natural products - gives us interesting compounds | Combinatorial chemistry |
| What is a hit? | Most initial compound | PK/binding to a target hasn't been optimized | ||
| What is a lead? | A hit that has been researched | May have PK/binding features | ||
| What is combinatorial chemistry? | Uses molecular scaffolds to construct libraries of similar compounds | Can synthesize and test mixtures of compounds in parallel | Cool instruments to run HTS | Success depends on complexity of library |
| What is a solid phase technique? | Reactions are carried out on solid support (i.e. resin bed) | Protective group prevents reactions from happening on a certain group | Link peptides and use acid to cleave off initial bead/peptide | |
| What is a bead-linker synthesis? | Bead: a penetrable polymer that "swells" and allows access to interior functional groups | Linker: a unit covalently attached to bead that constitutes solid support | Good for peptide synthesis | N-protected AA linked to resin via ester link |
| How does a split and mix work? | Produces a mixture of products in each reaction vessel | Makes large libraries of compounds | ||
| How does photolithography work? | Products made on a plate of immobilized solid support | Put a mask with holes and reveal locations of reaction | Light is exposed --> deprotected groups are revealed | Incubation of plate with fluorescent tagged receptor --> easy detection of active compounds |
| What is dynamic combichem? | Synthesize all compounds in one flask simultaneously and ID most active ones as they're being formed | Amplifies active compounds | Alternative to split and mix approach | Target molecule selects out ligand from equilibrium mixture --> shifts population |
| What is a vancomycin dimer? | Include tripeptide substrate --> increase rate of "bridge formation" and promote dimer formation | Binds to biochemical precursors | Doesn't inhibit a protein/receptor | |
| What are protein kinases? | Catalyze phosphorylation reactions on protein substrates | Found in cytoplasm | Overexpression --> cancer | |
| What are the 3 classes of protein kianses? | Tyrosine kinases | Serine-threonine kinases | Histidine kinases | |
| What is the structure and function of the active site of protein kinases? | Contains binding site for protein substrate and ATP cofactor | Targeted by clinically useful inhibitors | Similar, but not identical for all protein kinases | |
| What is a Gefitinib? | A kinase inhibitor based on ATP | Aniline binds to hydrophobic pocket, which isn't taken advantage of by ATP | Blocks binding of drug molecule with kinase | Doesn't mess with ability to bind ATP |
| What are some challenges of Gefitinib analogs? | Gefitinib analog: drug-resistant mutation of Thr-->Met in binding site | Produces a steric clash with drug | Met blocks active site where drugs normally bind | |
| What are suicide inhibitors? | T338M: drug-resistant mutation | Irreversible inhibitor is active against T338M mutation | Covalently attaches to kinase and still be active against mutation | |
| What is the key concept of AbI and Src? | Structures look more different in inactive state than in active state | Drug binds inactive state --> increase selectivity | ex: Imatinib (a protein kinase inhibitor selective for Bcr-AbI which is active in tumor cells) | |
| What is angiogenesis? | When tissue is large enough, it creates its own vascular system | ex: VEGF | ||
| What are oncogenes? | Regulators of cell communication with outside environment | Derived through mutation of proto-oncogenes | stimulated by exposure to carcinogens --> cancer | |
| What are the functions of tumor suppressor genes (anti-oncogenes)? | Halt uncontrolled growth | Suppressed/inactivated --> cancer | ex: p53 | |
| What is the role of p53 in cancer? | A tumor suppressor gene that prevents cancer | Triggers cell cycle arrest/apoptosis by: oncogene activation, DNA damage, cellular stress | ||
| What are some common defects in cancer? | Abnormal signaling: can change growth factor/chemical messengers; make growth factor receptors constantly on --> insensitivity to growth inhibition | Abnormal cell cycle regulation: cyclins/cyclin-dependent kinases/inhibitors can change which cycle cell should be in | Abnormal chromosome maintainence: telomere stabilizes and protects DNA; telomerase keeps chromosome ends from shrinking | Abnormal and increased angiogenesis: as tumor grows, it grow its own vascular system via extending existing capillaries |
| What are DNA cross-linking agents and their role in anti-cancer drugs? | Extremely reactive electrophilic reagents | React with DNA nucleobases, which get alkylated | Aromatic N mustards are less reaction --> permits oral administration and transport by AA transporters --> ADME | Halogen = Cl |
| What are some DNA intercalating agents and their functions? | Dactinomycin: minor groove binding; complex is very stable --> prevents unwinding | Doxorubicin: major groove binding; charged AA group on sugar is important because phosphate backbone is negatively charged | Morpholino doxorubicin: morpholino increases solubility; better interactions with DNA --> more efficacious | |
| What are antimetabolites and their role in anti-cancer drugs? | Methotrexate with dihydrofolate reductase (DHFR) and NADPH - required for DNA synthesis | 5-fluorouracil - inhibits thymidylate synthase | Inhibits cell metabolism of pathogen; host's metabolism remains unaffected | |
| What is Tamoxifen? | A hormone antagonist of (o)estrogen receptor in breast tissue | Prevents binding of (o)estradiol | Take 1-2 pills/day, but don't exceed 6 months | |
| What is Aromatase? | A hormone-based therapy that catalyzes biosynthesis of androgens --> estrogens | Uniquely highly substrate specific | An example of a non-metabolizing P450 | Inhibition --> chemotherapy for estrogen-dependent breast cancer |
| What is Femara (Letrozole)? | A reversible competitive inhibitor of aromatase | Binds to other CYP450 --> undesirable side effects | Prescribed after 6 months of taking Tamoxifen | |
| What is Herceptin (Trastuzumab)? | Monoclonal antibody that binds to HER2 (Human Epidermal growth factor Receptor 2) | |||
| How does Herceptin compare to Femara? | More specific (using antibodies vs. small molecules) | More expensive (making antibodies costs money) | Can alter receptors in heart, if taken for too long | PK issues; very big structure --> can't cross BBB --> may cause brain cancer |
| When would Herceptin not work? | No HER2 gene | When receptor is mutated | When cancer has progressed to a point beyond treatment (stage 4) | When cancer is constitually active (whether messenger is present or not, receptor is turned on) |
| What is cell wall biosynthesis? | Building block is constructed from 2 sugars (NAG, NAM) + peptide chain in cytoplasm | Transported across cell membrane and completed | Linked to growing cell wall by enzyme (transglycosidation) | Final cross-linking reaction catalyzed by transpeptidase enzyme |
| What is penicillin? | An antibacterial agent that inhibits cell wall synthesis | |||
| How does penicillin work? | Inhibit a bacterial enzyme (transpeptidase) involved in synthesis of bacterial cell wall | b-lactam ring involved | Covalently link to enzyme's active site --> irreversible inhibition | |
| How do Gram +/- cell walls influence penicillin? | Gram +: thick, but porous cell wall; no hydrophobic barrier --> more susceptible to penicillin | Gram -: Has a thin cell wall and a hydrophobic layer --> less susceptible to penicillin | ||
| What are the problems with penicillin? | Sensitive to stomach acids | Sensitive to b-lactamases (enzyme that hydrolyze b-lactam ring) | Has a limited range of activity | |
| How is penicillin's sensitivity to b-lactamases a problem? | Opens b-lactam ring --> inactivates penicillin | Allows bacteria to be resistant to penicillin | Transferrable between bacterial strain | |
| How does penicillin's sensitivity to b-lactamases work? | Blocks access of penicillin to active site of enzyme by introducing bulky groups to side chain | Size of shield is important to inhibit reaction of penicillins with b-lactamases | ||
| What is a pharmacaphore? | Abstract description of molecular features necessary for recognition of a ligand by a receptor | Maps important sites to target | Can be ligand-based/receptor-based | |
| What is docking? | Prediction of a ligand conformation/orientation within a binding site | |||
| What is AutoDock? | A rough estimate of a protein's free energy | Freezes protein --> dock structure | Restrain free molecule --> increase binding affinity |
Created by:
julie_ahhh
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