med chem – Chemistry – Flashcards

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question
what are some protein protein interaction examples
answer

cellular structure
immune response
signal transduction
apoptosis (cell death)

question
even though protein protein interactions don't contain covalent bonds why are they able to have such strong ;bonds
answer
because of the large surface areas that interacy
question
what is the hotspot in protein protein interactions
answer
patches of area on the amino acid that have hydrogen bond doner/acceptor
question
can your inhibitor work if it does not have the same or more favorable bindining affinity as the substrate
answer
yes if you have a higher concentration
question
do you need to know the entire protein structure to block binding of proteins
answer
no you can target enzyme active sites
question
explain how target based drug design narrows down the library of molecules
answer
Experimental screening (competitive binding, enzyme assay, fluorometry) and computational screening;
question
what is peptidomimetics
answer
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)
question
when do you use partial atomic charges
answer
when dealing with H bonds (accounts for the dipole moment)
question
why use;peptidomimetics
answer
this is because you will have the save binding points to compete with your protein
question
what are some challenges for developing PPI
answer

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.

question
why is ERK a great target for drug design
answer

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)

question
how does signal transduction relate to drug design
answer
 this is typically a good target for PPI inhibitors
question
what is HCK
answer
a non receptor tyrosine kinase that is part of a signal transduction pathway for cell proliferation
question
what are the targets for PPI
answer

transcription factors (BCl6 in cancer)

signal transduction pathways ( Erk of the mitogen pathway,

and HCK of the SRC family

question
why target DNA transcription factors for PPI
answer
cancer has a misregulation of these
question
what are two important methods of developing inhibitors of protein protien interactions
answer

target based

peptidomimetics

question
what is the first protein based drug
answer
insulin
question
in 1977 we cloned somatostatin what is this called
answer
genetic engineering
question
what is erythropoietin
answer

i ) Kidney glycoprotein that stimulates growth of red blood cells in bone marrow
ii) Approximately equal mass of protein (34
kD) and carbohydrate
iii) Used in anemia
iv) Abused by athletes

question
what are some examples of biotech drugs
answer

erythropoeitin

blood factors

growth factors

human growth hormone

cytokines

enzymes (adenosine deaminase

MABS

question
describe what human growth hormone is
answer

i) From pituitary gland, used for growth deficiencies in children (nanism, dwarfism)
ii) Hormone originally isolated from human cadaver pituitary (Creutzfeldt-Jakob syndrome)

question
what is somatotropin
answer
this will cause the release of human growth hormone
question
explain what cytokines are produced as a drug
answer

i) Interleukins (ILs)
    a) Immune system hormones
    b) Interleukin-11 (rhIL-11,
oprelvekin, Neumega, Genetics Institue) for treatment of Chemotherapy induced Thrombocytopenia

     ii) Interferons

          a) Generally antiviral, antiproliferative and immunomodulatory effects.
    b) Interferon Beta-1A and 1B: used in treatment of relapsing multiple sclerosis

question
what are the issues with protein based drugs
answer

1) Antigenicity (non self vs self)

2) Stability

3) Drug Delivery

the protein needs to have the appropriate 3D structure

question
how do we get around antigeneicity in MABs
answer

i) chimeric antibodies
    ii) antibodies produced in transgenic mice, rats or yeast

        iii) phage display antibodies

question
what contributes o instability in protein drugs
answer

   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

question
how can you help preserve protein drugs
answer

c) Protein often more stable in dry form (lyophilized)

d) Additives to enhance stability

e) Detection of instability

question
what methods do you use to measure the stability of a recombinant protein
answer

  1. SDS page-detecs frafmentation, crosslinking, oligomerization
  2. RP-HPLC- deamidation, crosslinking, methionin oxidation, disulfide scrambling
  3. IEF- deamidiation
  4. potency determination- disulfide scrambline (most important)

question
what are some issues with drug delivery of protein drugs
answer

hard to give without denaturation (chemical alteration)

rapid liver clearance

question
what are some solutions to drug delivery pproblems with protein based drugs
answer
give drugs parenterally, nasal, implants, use microspheres for sustained release, inhalers
question
what kind of changes would you see in a 2nd generation protein based drug
answer
      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
question
what will maintain a proteins 3d structure when it is dried out
answer
glycosylation (sugars)
question
what receptor recognizes the carbs on the surface of a protein
answer
asialoglycoprotein receptor (basically there to replace damaged proteins)
question
why would you pegylate your protein
answer
this should decrease clearance and thus increase efficacy
question
what are some sources of protein products
answer

E.coli

yeast

mammalian cells

transgenic animal/ plant sources

 

question
what are some charecterisitcs of using E.coli to produce your proteins
answer

i) Cheapest
ii) No glycosylation or
disulphide formation
iii) Fusion proteins

      iv) Met at N terminus of the
v) Toxins (gram positive bacteria) in
E.Coli

question
what are some charecteristics of using yeast to make your proteins
answer

i) Relatively inexpensive
ii) Hyper or incorrectly glycosylates

      iii) Correct disulfides 
iv) No toxins
v) Proteins excreted into medium

question
what are some charecteristics of using mammalian cells to produces your proteins
answer

i) Most expensive of cell-based methods
ii) Produces the most active protein due to proper modifications
iii) Proper post-translational modifications

          glycosylation
    phosphorylation
    disulfides
   
propeptide processing

question
what is the deal with using transgenic animals as a source for proteins
answer
insert a gene so that the animal will express the protein of interest and maybe secrete it in it's milk or egg
question
in a protein based durg is it easier to prove bioequivelance
answer
no since you have very subtle changes in production that alter bioequivelance
question
what does an antisense oligodeoxynucleotide do
answer
it binds to the DNA strand to block expression of the protein
question
what is the difference betweent antisense and sens agents
answer
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
question
if you increase the length of an antisens agent what increases and what decrease
answer

affinity increases (and your able to miss a pair)

you decrease specificity

question
what is the magic number to max affinity before you lose specificty
answer
15 base pairs
question
in a antisense agent what type of base pairs will increase affinity
answer
G/C 
question
what are some antisense targets
answer

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

question
in leukemia how can use antisense agents
answer

remove the bad bone marrow and replace it with good bone marrow

kill the leukemia cells in the bone marrow

question
how does an antisense agent work at the DNA level
answer

blocks transcription by forming a triplex (three strands)

 works at single strand to form a bubble

question
how is the antisense agent going to work on the mRNA level
answer

during synthesis

at the intron exon junction

inhibits protein initiation factors

question
how does an antisense agetn work to block ribosome interactions
answer

at the start codon

and overall interactions

question
what are some issues with antisens development
answer

absorption (limited ability to cross membaranes

stability

affinity to binding

question
how can you enhance antisense products uptake
answer

co-admin with cationic lipids

encapsulation in carbs

chimeric molecules

alternate backbones (with methylphosphonate)

question
how can you increase stability of antisense products
answer

block 3 prime exonuclease activity

sub the phosphodiesterase bond with a peptide bond

 

question
what kind of sugar modifications can you make to antisense molecules
answer

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)

question
what kind of base modifications can you make to your antisense molecules
answer

Hydrophobic modifications of 5' position of pyrimidines that enhance affinity for target RNA or DNA

question
what is interference RNA
answer
a molecule that forms a duplex of with mRNA then it degrades it (this ultimately causes gene silencing)
question
how do they deliver interference RNA
answer
give it a short hairpin then once it gets into cell the dicer will cut it up
question
what is a ribozyme
answer
RNA molecules that assume tertiary structures and have the ability to catalyze chemical reactions, making them catalysts
question
what are some applications of ribozymes
answer

target HIV

and lower expression  of MDR (transporters that eject drug from cell)

question
what are goals of target based drug design
answer

1) Understand atomic details of drug binding strength and specificity

 
2) Identify or create novel molecules to bind to a selected target and elicit a biological response via de novo drug design or database searching techniques


3) Optimize the therapeutic index of an already available drug or lead compound

question
what stabilizes a beta sheet 
answer
the bond between the carbonyl and the NH group
question
where can you find a prosthetic group
answer
in vitamins (tertiary structure)
question
what kind or receptor is rhodpsin
answer
G-protein coupled receptor
question
what is molecular modeling
answer

3D representation of molecules based on graphic or mathematical representations of chemical structures

question
what is quantum mechanics
answer

treat electrons explicitly

limited to 100 atoms

question
what is molecular mechanics
answer

deals with atom as smallest particle

every atom interacts with ever other atom

allos you to study a system with millions of atoms

question
what is the empiracal energy finction
answer

V total=Vinternal+Vexternal

where Vinternal=Vbonds+Vangles+Vdihedrals

Vexternal=Vvanderwaals+Velectrostatic

question
what is dihedral angle talking about
answer
rotation about the central bond
question
when looking at the COS function for a dihedral bond how can you tell the difference between a single bond and double bond
answer

double bond has 2 peaks (a peakseperated by 180 degrees)

in a single bond you have 4 peaks (each peak seperated by 60 degrees)

question
when looking at the van der waals energy diagram what happens to attractive forces and repulsive foces
answer

the closer you get the less your attractive forces are

the closer you are the greater your repulsive forces

question
for a double bond how many maxima and minima are there
answer
2
question
if a molecules graph (dihedral angle vs potential energy goes to 0 at 0 degreess and 360 how many global minima are there
answer
1
question
what is energy minimization
answer
figuring out how to alter your structure to get to the lowest energy level (must go from energy to force)
question
what happens to force the further away from the minima you are
answer
the more posative or negative it becomes
question
how do you figure out how many degrees of freedom you have
answer
the amoung of conformations raised to the power of the amount of atoms are in the molecule
question
how long can you predict movement in an atom of a molecule
answer
fentos second (10to the -15S)
question
MD simulations can give you what values
answer
entropy but ultimately free energy
question
what info is required for calculations of energy for minimization and for molecular dynamics
answer

energy (atom positions)

energy minimizations (atoms positions, forces)

molecular dynamic simulation (atom simulation, forces, atomic velocities)

question
what id docking (database searching)
answer
screening through a list of none compounds to see if they will bind to your site
question
what is de novo design
answer
design novel compounds by putting diffrent pieces together to fit your recteptor
question
what is pharmacophore
answer

geometric arrangment of functional groups

can be determined by 3d structure, knowledge of ligand

question
what is grid in relation to pharmacophore
answer

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

question
in a grid what yields a pharmacophore
answer
types of functional groups and their positions
question
what counter acts a dipole
answer
solvation energy this may facot for example a carbonyle
question
explain what docking is
answer
Computationally identify compounds with a high probability of binding to a site on a protein or RNA
question
what are the steps in docking
answer

  1. determine solvent accessible surface of binding pocket (spheres)
  2. generate a negative image of receptor based on spheres
  3. determin sphere distances of the negative image
  4. convert sphere distances to atom distances
  5. compare atom distances with actual atom distances
  6. select ligands with greatest overlap
  7. calculate ligand receptor interaction energies

question
what is groupbuild
answer
this is a de novo computer program that builds a molecule up from scratch to the receptor
question
how do you perform a group build
answer

  1. develop a grid for binding site (include electrostatic, VDW)
  2. generate a structures (first is the core, then you build up on it then randomly select one of the top 25%
  3. synethesise compounds

question
how do analyse yo'u groupbuilt structure
answer
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!).

question
what are the limitations of database screening and de novo design
answer

 

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

 

question
how do you perform lead compound optimization
answer
use free energy perturbation 
question
what are the steps involved in drug receptor interactions
answer

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

question
what is Thermodynamic cycle applied to relative binding of two inhibitors
answer

a method to compare 1 drug receptor complex to another

Keq2/Keq1=Kreceptor/Ksolution

question
how is alchemical perturbation performed
answer

  1. in a computer you change molcule 1 that is bound to the receptor to molecule 2 in the receptor
  2. this is done by change the equilibrium and force constants in small steps

question
why perform alchemical perturbation since in reality you can't do it
answer
since you can just develop the final product (the final state is the only thing that matters)
question
how does free enery component analysis work
answer
you will essentially add up all the portions that contribute to the whole
question
Dihydrofolate Reductase is a target for drugs why
answer
it is involved in synthesis of DNA and can be a target to stop cancer
question
what diseases are Dihydrofolate Reductase targets involved in
answer

1) Anticancer agents

2) Antibacterials

3) Non-surgical abortions

question

Dihydrofolate Reductase uses what as an electron source

answer
NADPH
question
what makes up Dihydrofolate Reductase, and which are good targets for drugs
answer

glutamic acid

benzoic acid

bridge

pteridyl

the drug target is the pteridyl

question
what are the three different types of Dihydrofolate Reductase inhibitors
answer

  1. amino pteridine (competative inhibitor)
  2. methotrexate (just adds a cabonyl to the amino group of the pteridyl )
  3. trimethoprim

question
why use natural products
answer

  • we evolved with them
  • chemistry is similiar
  • diverse plants and diverse chmistry as a result
  • tend to be nourshing and supportive

question
what is the doctrine of signature
answer

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

question
why eat organs
answer
some cultures believe that eating an organ will give you a healthy organ kidney for enhanced kidney
question
what were some other uses of natural producte
answer

  1. arrow poison
  2. religous rituals (phyostigma
  3. belladonna oracle of apollo, and cosmetics
  4. as corecers drug

 

question
traditional chinese med started by shen nung used what
answer

wormwood against malaria, fever

toad skin for heart conditions (digitalis glycosides)

used ephedra sinica as stimulant

question
what is pen tsao kang mu
answer
this is a book of chinese traditional meds compiled in the ming dunasty
question
what is the ebers papyrus
answer

16th century book on its meds

 

question
what are some herbals that were dated back to egypt
answer
aloe and poppy seeds
question
where was snake root used first
answer
india
question
what laid the foundation of western medicine
answer
ancient greeks (hippocrates esp)
question
what is de materia medica
answer
this was a compliation by roman dioscorides that had over 600 species of plants with medical values
question
whats the deal with mandrake
answer
it was used as a pain killer anesthatic
question
how did islam contribute to medicine
answer
pharmacy had the highest reputation in arab world, and was the first time it was independent
question
where was the fist pharmacy
answer
baghdad in 8th centurary
question
what is hindiba
answer
a plant to treat cancer
question
what is black seed
answer

regarded as the greatest form of healing med in islam

now it is none to have many of the nutrients reccomended by the FDA

question
the start of the renasissance rang in
answer
the age of herbals
question
how many americans use CAM
answer

40% of american population

73% of cancer patients

question
what is the largest part of CAM
answer

herbal medicine

ingested

aroma

ointments

question
what is the problem with herbals branded as supplements
answer

labeling issues

no quality control

misinformation in literature

question
are herbal meds standarized (guranteed to have certain amount of active ingredient)
answer
some are some are not
question
what are the top three challenegs with herbal products
answer

supply issue

quality issue

safety issue (herbal drug food interactions)

question
thermogenics are herbs to control weight loss what is the most common
answer

caffeine

followed by ephedra

question
what is nother name for ephedra
answer
brigham tea
question
what is fo-ti root
answer

long life elixer

reverses gray hair, ED, vaginal discharge

question
research on fo-ti root revealed what
answer

it may lower cholesterol

mild laxative

question
what is bay chi root supposed to do
answer
be an antioxident lower blood pressure
question
what is konjac used for
answer
reduce appetite, regulate insulin, help with weight, regulate LDL cholesterol
question
what can apple cider vinegar do for you
answer

weight loss

lower blood pressure

reduce cholesterol

fight arthritis pain

relief sore throat

question
glucosamine is safe for regular use for how long
answer
4 years
question
what is SAMe used for
answer
depression arthritis liver disease heart disease
question
what are the top ten herbals
answer

Ginko

echinacea

garlic

ginseng

soy bean

saw palmetto

st john's wort

valerian

bilberry

black cohosh

question
what is active ingredient in ginko and is effective for what
answer

increase blood flow

possibly effective in dementias

only safe for a year use

question
when should you not use ginko
answer
with caffeine and stimulants, with antiplatelets
question
what does echinacea do for you
answer

produces nonspecefic immune activation

use with flu

question
how long can you use echinacea for
answer

12 weeks

8 weeks in autoimmune disease

question
why not use long term
answer
can be immunosupprsive and in autoimmune disease will exacerbate symptos
question
what is garlic used for
answer

active ingredient allicin will lower lipids and cholesterol

 

question
how should you take garlic
answer
enteric coated since it will be destroyed by gastric acid
question
what is ginsing used for
answer
possibly effective for improved cognitive function, type 2 DM, bronchitis
question
how should you use ginsing (how long)
answer
3 months on and a period off
question
what are some interactions of ginsing and precautions
answer

interacts with lasix, inhibit barbitutes

may increase BP and overuse can give insomnia headaches etc..

question
what is soybean used for
answer
estrogen replacement
question
what is saw palmetto used for
answer
helps relieve stage 1 and 2 BPH due to anti-teterterone action
question
what can you use st. johns wort for
answer
may work on mild to moderate depression
question
what are some contraindications to st johns wort
answer

sever depression, suicidal tendencies, sever agitation, prego, may induce seratonin syndrome with triptans, mat interfere with cyclosporin, inhibits CYP450

may cause photosensitvity

question
what do you use valerian for
answer
sleep sedation
question
what is black cohosh used for
answer
relieved premenstrual symptoms
question
what is milk thistle used for
answer
used to help chronic liver disorders
question
what is ginger used for
answer
anti emetic antimotion sickeness
question
what percentage of drugs are derived from natural products
answer

about 25%

74% of anticancers

78% of anti-bacterial

question
why has natural products for drugs been on the decline
answer
 incompatablity with HTS
question
what are natural products as drug sources
answer

natural products produced in cells

primary metabolites

secondary metoblites

question
what are lipinski's rule of 5 for oral drugs
answer

 

 

  1. Not more than  ?5 H bond doners (OH and NH groups) 
  2. hydrogen bond acceptors  10 (5X2) Not more than (notably N and O) 
  3. A molecular weight under 500 (5x100)  ?
  4.   A partition coefficient logP 5 under
  5. < then 10 rotatable bonds

 

 

question
what are the three most common toxic substances within herbals
answer

pyrrolizidine alkaloids

phorbal esters

aristolochic acids

question
what is wrong with BOrage
answer

it can be teratogenic, carcinogenic, hepatoxic

contains pyrrolizodine alkaloids

question
what is wrong with sweet flag
answer
contains cis-isoasarone that is a carcinogen
question
what is wrong with chaparral
answer

is nephrotoxic and hepatotoxic

contains NDGA

question
what is wrong with coltsfoot
answer
hepatotoxic pyrrolizidine alkaloids
question
what is wrong with comfrey
answer
this is hepatotoxic due to pyrrolizadine alkaloids
question
what is wrong with germander
answer
 hepatotoxic due to diterpenoids
question
what is wrong with licorice
answer

it is a pseudoaldosteronism (retains Na, water and depletes K)

this is dose dependent

question
what is wrong with poke root
answer
this is highly toxic to organs due to triterpenoid saponins
question
what is wronge with sassafras
answer
contains safrole which is a carcinogen
question
rule of thumb for herbals
answer

 Avoid using herbs in 

infants, children, pregnant women, 

nursing mothers, patients w/ daisy 

allergies, patients on multiple 

medications

question
herbals can effect drugs how
answer

they can alter transporters

they can alter CYPS

alter absorption

compete with drug targets

question
what drug interacted with saquinavir
answer
Garlic
question
how does St.Johns wort affect CYPD3A4
answer
it will induce it
question
what are the applications of QSAR
answer

classification

diagnosis of mechanisms of drug action

prediction of activity (in congeneric series)

lead compound optimization

question
how did we make sulmazole stop giving us halucinations
answer
used QSAR to do a bio-isoteric replacement lowreing coefficient to 1.2 so it dind't cross BBB
question
what is the hammemett electronic parameter (σ)
answer
this will tell you the electron donatin or withdrawing properties
question
what does a positive σ tell you
answer
that you have an electron withdrawing group and increase Ka
question
what does a negative σ
answer
it is electron donating  and it will decrease Ka
question
when you substitute at the para position how will this effect the ring, how about ortho and meta
answer

  1. the ortho position will have minimal transferability
  2. the meta position will have an inductive effect (may favor unionized thus smaller Ka) a -σ
  3. if you have a para substituant then you will have resonance effects(increasing Ka) a +σ

question
what is the general utility of σ values
answer
it allows you to predict it's value and contribution for similiar compounds
question
when graphing σ what is a posative slope and a negative slope
answer

the posative slope is an electron withdrawing group

the negative group is electron donating

question
what is tafts seric parameter
answer

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)

question
what does molar refractivity tell you
answer
the molar refractivity goes down as the molecule becomes more dense and this is better
question
how can we apply QSAR to the biologic system (biological hammet relationship)
answer

Consideration of need to cross membranes

Blood brain barrier

Lipophilicity (hydrophobicity)-this will dictate how fast it can cross the barrier

question
what is the hydrophobicity
answer

if it is + then it will be more hydrophobic

if it is- it will be more hydrophillic

question
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
answer
.5+.5+interaction factor
question
when you use the linear equation you will have a final K what is this
answer
this the activity of the unsubstituted compound
question
if you want to increase activity what do you want ∏ to be and σ
answer

  1. ∏ you will want this to be negative, but not so much to where it wont go into the lipid bilayer (more hydrophillic)
  2. σ you will want this to be posative (electron withdrawing)

question
what is the disadvantage of hansch equation
answer

hard to extrapolate byond your list

predictions are limited to rings

you will need 5 compounds for every term you use

question
what is the spanned substituion space
answer
range of physical properties covered by the compounds in the training set (QSAR)
question
the free wilson model tells you what
answer

it's like an on off switch

I is substituant and J is location

question
what is the topliss decision tree
answer

  • basically trying to find your drug without using a training set
  • measure then add what you think is needed measure then keep doing this till you are close to what you want

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