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CHEM 167

Medicinal Chemistry Final

QuestionAnswer
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