Medicinal Chemistry Final
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| What is the significance of molecular orbitals? | Tells us something about molecular reactivity | Can be calculated through quantum mechanics | Care about where electrons are |
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| What is the significance of molecular dynamics? | Used to probe structure and dynamics | Don't care where electrons are |
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| What is High Throughput Screening (HTS)? | Actual experimental approach that tests tons of compounds to find a hit | Very rapid way of performing synthesis |
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| What is virtual screening? | Only test top compounds that will actually be likely binders | Predicted from a computer |
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| 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
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| What is a hit? | Most initial compound | PK/binding to a target hasn't been optimized |
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| What is a lead? | A hit that has been researched | May have PK/binding features |
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| 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
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| 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 |
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| 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
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| How does a split and mix work? | Produces a mixture of products in each reaction vessel | Makes large libraries of compounds |
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| 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
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| 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
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| 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 |
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| What are protein kinases? | Catalyze phosphorylation reactions on protein substrates | Found in cytoplasm | Overexpression --> cancer |
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| What are the 3 classes of protein kianses? | Tyrosine kinases | Serine-threonine kinases | Histidine kinases |
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| 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 |
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| 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
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| 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 |
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| 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 |
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| 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) |
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| What is angiogenesis? | When tissue is large enough, it creates its own vascular system | ex: VEGF |
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| What are oncogenes? | Regulators of cell communication with outside environment | Derived through mutation of proto-oncogenes | stimulated by exposure to carcinogens --> cancer |
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| What are the functions of tumor suppressor genes (anti-oncogenes)? | Halt uncontrolled growth | Suppressed/inactivated --> cancer | ex: p53 |
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| 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 |
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| 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
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| 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
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| 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 |
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| 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 |
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| 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 |
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| 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
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| What is Femara (Letrozole)? | A reversible competitive inhibitor of aromatase | Binds to other CYP450 --> undesirable side effects | Prescribed after 6 months of taking Tamoxifen |
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| What is Herceptin (Trastuzumab)? | Monoclonal antibody that binds to HER2 (Human Epidermal growth factor Receptor 2) |
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| 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
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| 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)
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| 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
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| What is penicillin? | An antibacterial agent that inhibits cell wall synthesis |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| What is docking? | Prediction of a ligand conformation/orientation within a binding site |
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| What is AutoDock? | A rough estimate of a protein's free energy | Freezes protein --> dock structure | Restrain free molecule --> increase binding affinity |
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