med chem – Chemistry – Flashcards
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Unlock answers| what are some protein protein interaction examples |
cellular structure immune response signal transduction apoptosis (cell death) |
| even though protein protein interactions don't contain covalent bonds why are they able to have such strong ;bonds |
| because of the large surface areas that interacy |
| what is the hotspot in protein protein interactions |
| patches of area on the amino acid that have hydrogen bond doner/acceptor |
| can your inhibitor work if it does not have the same or more favorable bindining affinity as the substrate |
| yes if you have a higher concentration |
| do you need to know the entire protein structure to block binding of proteins |
| no you can target enzyme active sites |
| explain how target based drug design narrows down the library of molecules |
| Experimental screening (competitive binding, enzyme assay, fluorometry) and computational screening; |
| what is peptidomimetics |
| Inhibitors based on primary or secondary structure of the part of the partner protein that participate in PPIs ;(this means you will conserve the key parts) |
| when do you use partial atomic charges |
| when dealing with H bonds (accounts for the dipole moment) |
| why use;peptidomimetics |
| this is because you will have the save binding points to compete with your protein |
| what are some challenges for developing PPI |
1.Natural small molecules known to bind at protein ; protein interfaces are rare --> no template available for designing antagonists 2.Difficult to locate small, deep cavities that could make good small-molecule binding sites from X-ray structures 3.Assaying inhibition is difficult in contrast to enzyme inhibition (recall Michaelis-Menten: competitive vs. allosteric antagonists of enzyme activity) 4.Therapeutic antibodies although effective (e.g. Herceptin), are not cell-permeable and so cannot be given orally 5.“Hot spots” appear to have conformational flexibility, and can adapt from a near-flat surface to a cavity capable of binding a small molecule. |
| why is ERK a great target for drug design |
nActive in cell proliferation in many types of cancers nCrystal structures of the active and inactive form are available nMutagenesis studies have discovered residues important for binding to its substrates (blue and green) |
| how does signal transduction relate to drug design |
| this is typically a good target for PPI inhibitors |
| what is HCK |
| a non receptor tyrosine kinase that is part of a signal transduction pathway for cell proliferation |
| what are the targets for PPI |
transcription factors (BCl6 in cancer) signal transduction pathways ( Erk of the mitogen pathway, and HCK of the SRC family |
| why target DNA transcription factors for PPI |
| cancer has a misregulation of these |
| what are two important methods of developing inhibitors of protein protien interactions |
target based peptidomimetics |
| what is the first protein based drug |
| insulin |
| in 1977 we cloned somatostatin what is this called |
| genetic engineering |
| what is erythropoietin |
i ) Kidney glycoprotein that stimulates growth of red blood cells in bone marrow |
| what are some examples of biotech drugs |
erythropoeitin blood factors growth factors human growth hormone cytokines enzymes (adenosine deaminase MABS |
| describe what human growth hormone is |
i) From pituitary gland, used for growth deficiencies in children (nanism, dwarfism) |
| what is somatotropin |
| this will cause the release of human growth hormone |
| explain what cytokines are produced as a drug |
i) Interleukins (ILs) ii) Interferons a) Generally antiviral, antiproliferative and immunomodulatory effects. |
| what are the issues with protein based drugs |
1) Antigenicity (non self vs self) 2) Stability 3) Drug Delivery the protein needs to have the appropriate 3D structure |
| how do we get around antigeneicity in MABs |
i) chimeric antibodies iii) phage display antibodies |
| what contributes o instability in protein drugs |
deamidation: Asn, Gln oxidation: Met proteolysis: Arg, Lys racemization and acid labile: Asp disulfide exchange: Cys, disulfide aminolysis: Lys beta-elimination: Cys, Ser, Thr, Lys b) Proteolysis during storage due to enzymes associated with bacterial contamination |
| how can you help preserve protein drugs |
c) Protein often more stable in dry form (lyophilized) d) Additives to enhance stability e) Detection of instability |
| what methods do you use to measure the stability of a recombinant protein |
|
| what are some issues with drug delivery of protein drugs |
hard to give without denaturation (chemical alteration) rapid liver clearance |
| what are some solutions to drug delivery pproblems with protein based drugs |
| give drugs parenterally, nasal, implants, use microspheres for sustained release, inhalers |
| what kind of changes would you see in a 2nd generation protein based drug |
| i) Modification or removal of selected amino ii) Production via an alternate source (see below) iii) Deletion of unessential portion of the protein (e.g. Sermorelin) iv) Introduction of disulfide bonds v) Proper phosphorylation required for biological activity |
| what will maintain a proteins 3d structure when it is dried out |
| glycosylation (sugars) |
| what receptor recognizes the carbs on the surface of a protein |
| asialoglycoprotein receptor (basically there to replace damaged proteins) |
| why would you pegylate your protein |
| this should decrease clearance and thus increase efficacy |
| what are some sources of protein products |
E.coli yeast mammalian cells transgenic animal/ plant sources
|
| what are some charecterisitcs of using E.coli to produce your proteins |
i) Cheapest iv) Met at N terminus of the |
| what are some charecteristics of using yeast to make your proteins |
i) Relatively inexpensive iii) Correct disulfides |
| what are some charecteristics of using mammalian cells to produces your proteins |
i) Most expensive of cell-based methods glycosylation |
| what is the deal with using transgenic animals as a source for proteins |
| insert a gene so that the animal will express the protein of interest and maybe secrete it in it's milk or egg |
| in a protein based durg is it easier to prove bioequivelance |
| no since you have very subtle changes in production that alter bioequivelance |
| what does an antisense oligodeoxynucleotide do |
| it binds to the DNA strand to block expression of the protein |
| what is the difference betweent antisense and sens agents |
| antisense you only need to develop a 1 dimensional drug (know the sequence of the DNA) where as in sens you need a particular 3-d structure |
| if you increase the length of an antisens agent what increases and what decrease |
affinity increases (and your able to miss a pair) you decrease specificity |
| what is the magic number to max affinity before you lose specificty |
| 15 base pairs |
| in a antisense agent what type of base pairs will increase affinity |
| G/C |
| what are some antisense targets |
Target genes at DNA or RNA level that code for i) proteins in microorganisms to kill invading organism ii) proteins specific to cancer iii) any undesired protein |
| in leukemia how can use antisense agents |
remove the bad bone marrow and replace it with good bone marrow kill the leukemia cells in the bone marrow |
| how does an antisense agent work at the DNA level |
blocks transcription by forming a triplex (three strands) works at single strand to form a bubble |
| how is the antisense agent going to work on the mRNA level |
during synthesis at the intron exon junction inhibits protein initiation factors |
| how does an antisense agetn work to block ribosome interactions |
at the start codon and overall interactions |
| what are some issues with antisens development |
absorption (limited ability to cross membaranes stability affinity to binding |
| how can you enhance antisense products uptake |
co-admin with cationic lipids encapsulation in carbs chimeric molecules alternate backbones (with methylphosphonate) |
| how can you increase stability of antisense products |
block 3 prime exonuclease activity sub the phosphodiesterase bond with a peptide bond
|
| what kind of sugar modifications can you make to antisense molecules |
i) Enhance stability and affinity: alpha-anomer at 1' position of 2'deoxyribose ii) Resistance to nucleases: 2-OH modifications of ribose including 2'methyl, 2'-allyl, or 2'-fluoro (also enhance affinity) |
| what kind of base modifications can you make to your antisense molecules |
Hydrophobic modifications of 5' position of pyrimidines that enhance affinity for target RNA or DNA |
| what is interference RNA |
| a molecule that forms a duplex of with mRNA then it degrades it (this ultimately causes gene silencing) |
| how do they deliver interference RNA |
| give it a short hairpin then once it gets into cell the dicer will cut it up |
| what is a ribozyme |
| RNA molecules that assume tertiary structures and have the ability to catalyze chemical reactions, making them catalysts |
| what are some applications of ribozymes |
target HIV and lower expression of MDR (transporters that eject drug from cell) |
| what are goals of target based drug design |
1) Understand atomic details of drug binding strength and specificity 3) Optimize the therapeutic index of an already available drug or lead compound |
| what stabilizes a beta sheet |
| the bond between the carbonyl and the NH group |
| where can you find a prosthetic group |
| in vitamins (tertiary structure) |
| what kind or receptor is rhodpsin |
| G-protein coupled receptor |
| what is molecular modeling |
3D representation of molecules based on graphic or mathematical representations of chemical structures |
| what is quantum mechanics |
treat electrons explicitly limited to 100 atoms |
| what is molecular mechanics |
deals with atom as smallest particle every atom interacts with ever other atom allos you to study a system with millions of atoms |
| what is the empiracal energy finction |
V total=Vinternal+Vexternal where Vinternal=Vbonds+Vangles+Vdihedrals Vexternal=Vvanderwaals+Velectrostatic |
| what is dihedral angle talking about |
| rotation about the central bond |
| when looking at the COS function for a dihedral bond how can you tell the difference between a single bond and double bond |
double bond has 2 peaks (a peakseperated by 180 degrees) in a single bond you have 4 peaks (each peak seperated by 60 degrees) |
| when looking at the van der waals energy diagram what happens to attractive forces and repulsive foces |
the closer you get the less your attractive forces are the closer you are the greater your repulsive forces |
| for a double bond how many maxima and minima are there |
| 2 |
| if a molecules graph (dihedral angle vs potential energy goes to 0 at 0 degreess and 360 how many global minima are there |
| 1 |
| what is energy minimization |
| figuring out how to alter your structure to get to the lowest energy level (must go from energy to force) |
| what happens to force the further away from the minima you are |
| the more posative or negative it becomes |
| how do you figure out how many degrees of freedom you have |
| the amoung of conformations raised to the power of the amount of atoms are in the molecule |
| how long can you predict movement in an atom of a molecule |
| fentos second (10to the -15S) |
| MD simulations can give you what values |
| entropy but ultimately free energy |
| what info is required for calculations of energy for minimization and for molecular dynamics |
energy (atom positions) energy minimizations (atoms positions, forces) molecular dynamic simulation (atom simulation, forces, atomic velocities) |
| what id docking (database searching) |
| screening through a list of none compounds to see if they will bind to your site |
| what is de novo design |
| design novel compounds by putting diffrent pieces together to fit your recteptor |
| what is pharmacophore |
geometric arrangment of functional groups can be determined by 3d structure, knowledge of ligand |
| what is grid in relation to pharmacophore |
this is a way to develop a pharmacophore by a) Prepare a 3D lattice of grid points encompassing the binding site b) Determine interaction energy of different types of functional groups with binding site at each grid point.
c) Select favorable interaction sites d) Determine relative spatial orientations of the selected interaction sites |
| in a grid what yields a pharmacophore |
| types of functional groups and their positions |
| what counter acts a dipole |
| solvation energy this may facot for example a carbonyle |
| explain what docking is |
| Computationally identify compounds with a high probability of binding to a site on a protein or RNA |
| what are the steps in docking |
|
| what is groupbuild |
| this is a de novo computer program that builds a molecule up from scratch to the receptor |
| how do you perform a group build |
|
| how do analyse yo'u groupbuilt structure |
A)Visual examination of structures for chemical feasibility B) Identify specific positions of certain functional groups etc. that my be related to a known pharmacophore C) Database screening for similar compounds in chemical databases (avoid synthesis!). |
| what are the limitations of database screening and de novo design |
Rigid geometry of receptor and ligand Ligands often treated as flexible Multiple conformations of receptor can partially overcome rigid representation Inherent assumptions and simplifications in molecular mechanics
|
| how do you perform lead compound optimization |
| use free energy perturbation |
| what are the steps involved in drug receptor interactions |
1) diffusion controlled encounter 2) initial Michaelis complex 3) desolvation of both inhibitor and binding site 4) conformational changes of both inhibitor and binding site upon binding 5) correct orientation between drug and receptor binding site |
| what is Thermodynamic cycle applied to relative binding of two inhibitors |
a method to compare 1 drug receptor complex to another Keq2/Keq1=Kreceptor/Ksolution |
| how is alchemical perturbation performed |
|
| why perform alchemical perturbation since in reality you can't do it |
| since you can just develop the final product (the final state is the only thing that matters) |
| how does free enery component analysis work |
| you will essentially add up all the portions that contribute to the whole |
| Dihydrofolate Reductase is a target for drugs why |
| it is involved in synthesis of DNA and can be a target to stop cancer |
| what diseases are Dihydrofolate Reductase targets involved in |
1) Anticancer agents 2) Antibacterials 3) Non-surgical abortions |
Dihydrofolate Reductase uses what as an electron source |
| NADPH |
| what makes up Dihydrofolate Reductase, and which are good targets for drugs |
glutamic acid benzoic acid bridge pteridyl the drug target is the pteridyl |
| what are the three different types of Dihydrofolate Reductase inhibitors |
|
| why use natural products |
|
| what is the doctrine of signature |
using a plant that mimics human anatomy or disease ex
Walnut for brain health • Red juice of bloodwort for blood disorders • Kidney-shape leaves of Hepatica to treat • kidney disease |
| why eat organs |
| some cultures believe that eating an organ will give you a healthy organ kidney for enhanced kidney |
| what were some other uses of natural producte |
|
| traditional chinese med started by shen nung used what |
wormwood against malaria, fever toad skin for heart conditions (digitalis glycosides) used ephedra sinica as stimulant |
| what is pen tsao kang mu |
| this is a book of chinese traditional meds compiled in the ming dunasty |
| what is the ebers papyrus |
16th century book on its meds
|
| what are some herbals that were dated back to egypt |
| aloe and poppy seeds |
| where was snake root used first |
| india |
| what laid the foundation of western medicine |
| ancient greeks (hippocrates esp) |
| what is de materia medica |
| this was a compliation by roman dioscorides that had over 600 species of plants with medical values |
| whats the deal with mandrake |
| it was used as a pain killer anesthatic |
| how did islam contribute to medicine |
| pharmacy had the highest reputation in arab world, and was the first time it was independent |
| where was the fist pharmacy |
| baghdad in 8th centurary |
| what is hindiba |
| a plant to treat cancer |
| what is black seed |
regarded as the greatest form of healing med in islam now it is none to have many of the nutrients reccomended by the FDA |
| the start of the renasissance rang in |
| the age of herbals |
| how many americans use CAM |
40% of american population 73% of cancer patients |
| what is the largest part of CAM |
herbal medicine ingested aroma ointments |
| what is the problem with herbals branded as supplements |
labeling issues no quality control misinformation in literature |
| are herbal meds standarized (guranteed to have certain amount of active ingredient) |
| some are some are not |
| what are the top three challenegs with herbal products |
supply issue quality issue safety issue (herbal drug food interactions) |
| thermogenics are herbs to control weight loss what is the most common |
caffeine followed by ephedra |
| what is nother name for ephedra |
| brigham tea |
| what is fo-ti root |
long life elixer reverses gray hair, ED, vaginal discharge |
| research on fo-ti root revealed what |
it may lower cholesterol mild laxative |
| what is bay chi root supposed to do |
| be an antioxident lower blood pressure |
| what is konjac used for |
| reduce appetite, regulate insulin, help with weight, regulate LDL cholesterol |
| what can apple cider vinegar do for you |
weight loss lower blood pressure reduce cholesterol fight arthritis pain relief sore throat |
| glucosamine is safe for regular use for how long |
| 4 years |
| what is SAMe used for |
| depression arthritis liver disease heart disease |
| what are the top ten herbals |
Ginko echinacea garlic ginseng soy bean saw palmetto st john's wort valerian bilberry black cohosh |
| what is active ingredient in ginko and is effective for what |
increase blood flow possibly effective in dementias only safe for a year use |
| when should you not use ginko |
| with caffeine and stimulants, with antiplatelets |
| what does echinacea do for you |
produces nonspecefic immune activation use with flu |
| how long can you use echinacea for |
12 weeks 8 weeks in autoimmune disease |
| why not use long term |
| can be immunosupprsive and in autoimmune disease will exacerbate symptos |
| what is garlic used for |
active ingredient allicin will lower lipids and cholesterol
|
| how should you take garlic |
| enteric coated since it will be destroyed by gastric acid |
| what is ginsing used for |
| possibly effective for improved cognitive function, type 2 DM, bronchitis |
| how should you use ginsing (how long) |
| 3 months on and a period off |
| what are some interactions of ginsing and precautions |
interacts with lasix, inhibit barbitutes may increase BP and overuse can give insomnia headaches etc.. |
| what is soybean used for |
| estrogen replacement |
| what is saw palmetto used for |
| helps relieve stage 1 and 2 BPH due to anti-teterterone action |
| what can you use st. johns wort for |
| may work on mild to moderate depression |
| what are some contraindications to st johns wort |
sever depression, suicidal tendencies, sever agitation, prego, may induce seratonin syndrome with triptans, mat interfere with cyclosporin, inhibits CYP450 may cause photosensitvity |
| what do you use valerian for |
| sleep sedation |
| what is black cohosh used for |
| relieved premenstrual symptoms |
| what is milk thistle used for |
| used to help chronic liver disorders |
| what is ginger used for |
| anti emetic antimotion sickeness |
| what percentage of drugs are derived from natural products |
about 25% 74% of anticancers 78% of anti-bacterial |
| why has natural products for drugs been on the decline |
| incompatablity with HTS |
| what are natural products as drug sources |
natural products produced in cells primary metabolites secondary metoblites |
| what are lipinski's rule of 5 for oral drugs |
|
| what are the three most common toxic substances within herbals |
pyrrolizidine alkaloids phorbal esters aristolochic acids |
| what is wrong with BOrage |
it can be teratogenic, carcinogenic, hepatoxic contains pyrrolizodine alkaloids |
| what is wrong with sweet flag |
| contains cis-isoasarone that is a carcinogen |
| what is wrong with chaparral |
is nephrotoxic and hepatotoxic contains NDGA |
| what is wrong with coltsfoot |
| hepatotoxic pyrrolizidine alkaloids |
| what is wrong with comfrey |
| this is hepatotoxic due to pyrrolizadine alkaloids |
| what is wrong with germander |
| hepatotoxic due to diterpenoids |
| what is wrong with licorice |
it is a pseudoaldosteronism (retains Na, water and depletes K) this is dose dependent |
| what is wrong with poke root |
| this is highly toxic to organs due to triterpenoid saponins |
| what is wronge with sassafras |
| contains safrole which is a carcinogen |
| rule of thumb for herbals |
Avoid using herbs in infants, children, pregnant women, nursing mothers, patients w/ daisy allergies, patients on multiple medications |
| herbals can effect drugs how |
they can alter transporters they can alter CYPS alter absorption compete with drug targets |
| what drug interacted with saquinavir |
| Garlic |
| how does St.Johns wort affect CYPD3A4 |
| it will induce it |
| what are the applications of QSAR |
classification diagnosis of mechanisms of drug action prediction of activity (in congeneric series) lead compound optimization |
| how did we make sulmazole stop giving us halucinations |
| used QSAR to do a bio-isoteric replacement lowreing coefficient to 1.2 so it dind't cross BBB |
| what is the hammemett electronic parameter (σ) |
| this will tell you the electron donatin or withdrawing properties |
| what does a positive σ tell you |
| that you have an electron withdrawing group and increase Ka |
| what does a negative σ |
| it is electron donating and it will decrease Ka |
| when you substitute at the para position how will this effect the ring, how about ortho and meta |
|
| what is the general utility of σ values |
| it allows you to predict it's value and contribution for similiar compounds |
| when graphing σ what is a posative slope and a negative slope |
the posative slope is an electron withdrawing group the negative group is electron donating |
| what is tafts seric parameter |
Es this says that the impact of the substiuant is dependent on size( the term is always negative and the more so it is the more steric hinderance) |
| what does molar refractivity tell you |
| the molar refractivity goes down as the molecule becomes more dense and this is better |
| how can we apply QSAR to the biologic system (biological hammet relationship) |
Consideration of need to cross membranes Blood brain barrier Lipophilicity (hydrophobicity)-this will dictate how fast it can cross the barrier |
| what is the hydrophobicity |
∏ if it is + then it will be more hydrophobic if it is- it will be more hydrophillic |
| say you have a functional group that adds a ∏ of.5 and the same thing next to it how would you calculate the overall effect |
| .5+.5+interaction factor |
| when you use the linear equation you will have a final K what is this |
| this the activity of the unsubstituted compound |
| if you want to increase activity what do you want ∏ to be and σ |
|
| what is the disadvantage of hansch equation |
hard to extrapolate byond your list predictions are limited to rings you will need 5 compounds for every term you use |
| what is the spanned substituion space |
| range of physical properties covered by the compounds in the training set (QSAR) |
| the free wilson model tells you what |
it's like an on off switch I is substituant and J is location |
| what is the topliss decision tree |
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