NPB 107 > Midterm 3 > Flashcards

Midterm 3 Flashcards

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1
Q

molecular targets of drugs speed

A

Ion channel = ms

GPCR= seconds

Kinase = minutes

NR = hours

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2
Q

Why are ion channels targets for drugs

A

Ion channels are fast signaling targets

—> change membrane potential
–> ion flow

—> cell excitability

–> seconds bigegst target class

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3
Q

Dose response curve

A

DOSE VS RESPONSE

–> EC50 = dose that producese s50% effect ( drug potency)

–> Therapeutic Index= TD50 ( toxic dose)/ ED50

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4
Q

Ion channel
structure

A

ion channel structure:

-seleective filter—> determine which ion pass

–GATE= open/close

—Pore= ion flow occurs —> down electrochemical gradient

Stimulus occurs
↓
gate opens
↓
ion enters pore
↓
selectivity filter allows only ( AA select) correct ion
↓
ion flows across membrane

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5
Q

Voltage-Gated Channels & Action Potentials

A

Steps:
1️⃣ Na channels open
2️⃣ Na influx
3️⃣depolarization

Then:
4️⃣ K channels open
5️⃣ repolarization

*Ion channels generate electrical signals in neurons.

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6
Q

structure– Voltage gate ion channels

A

Voltage sensor detects membrane voltage changes.

VSD ( s1-4)= voltage sensing domain

PD( s5-6) = pore domain

–> each 4 domains

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7
Q

Why a problem in drug selective

A

Ion channels have similar structure

–> hard to be subtype selective

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8
Q

Why multiple voltage sensors

A

Each VSD detects changes in —>membrane voltage.

When voltage changes:

—VSD move –> Pull on pore domain

– Pore domain pull —> Channel PORE Open

  • this is how gate is opened
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9
Q

Ion channel drug binding where

A

–> multiple binding site
–> sites ( 1-4)

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10
Q

Pore blockers

A

–plugging hole
–drug physically blocks pore

-no ions pass

( BIG = bidning)

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11
Q

Gating Modifiers

A

flipping switch

– drug changes opening probbaliyy

-affects gating ( VSD)

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12
Q

Flecainide

A

Blocks sodium channel

–flecainide = blocks sodium channel

–Verapimil = blocks calcium channel

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13
Q

Verapamil

A

blocks calcium channels

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14
Q

ziconotide ( prialt)

A

snail toxin
pore blocker of –> CA channel

used to treat resistant chronic pain ( SEVERE PAIN)

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15
Q

Protoxin-II

A

Tarantula toxin, Gating modifier of sodium–> NA
channels,

–Promise to develop treatments for chronic pain

  • use in pain research
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16
Q

Why toxins matter

A

nature evolved –> selective ion chnnale inhibitors

—> used to discover drug

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17
Q

What kinds of molecules can we design to modulate ion channels,

A

1.Small molecule drug

  1. peptide bodies

3.antibodies

4.nano bodies

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18
Q

small molecular drugs

A

small molecular drugs:

  • most medications mad from this
  • small organic chemicals

how

-enter central pore
-OR
-bind inside channel acidity ( aka pore blockers0

Advantages:
-oral drugs possible
- cheap
- cross membrane easily

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19
Q

peptide toxins

A

petide toxins:

-short proteisn ( produced by animals)

  • evolved to target ion channels

How?
- bind to voltage sensing domain–> modify gate

( ex toxins –> vSD–> stabilize close state –> channel cant open).

advantage:
-selectie
-stong binding
- reveal channel function

Cant be taken orally, pppoor membrane pernetrion, have to be inject o other delivery method

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20
Q

Antibodies

A

antibodies:

-large immune protéines

  • bind specific regions of protein ( EX ion channels. –Extracellcular domain ).
  • cant cross membrane).

Howe?
–> Bidns extracellular loop—block ligand bonding
–> stabilize close state
–> prevent channel open

Advantages:
-specific
long half life

  • poor tissue pepentraion
  • cant bcross blood brain barrier
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21
Q

nano bodies

A

-small antibody fragments
-used to stabilize port conformation

  • better tissue pentreion than antibody
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22
Q

Computational durg deign

A

–> create novel ion channel modualtrs

–> POSSIBLEc new cases of medications

-Difificyty –> aching large subtype selectivity

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23
Q

Protein Folding Problem

A

Protein folding problem:

–> protein start as linear chain of Amino Acids
BUT
–> proteins dont stay linear
–> they for into 3 dimensional struts

  • ## shape of proiiten det what it does ( enzymes, receptors, ion channels, antibodies)WHY FOLDING MATTERS?
    –> ion channels = proteins in membrane

–>. if u dont now structure = cant desiring drug to bind

-> hard bc it folds in numerous ways

but folding follow energy landscape -=–> want low energy cofnomciaiton.

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24
Q

Protein Structure Determination

A

X-ray crystallography= diffraction

Nuclear Magnetic Resonance,= magnetic fields

Cryo-electron microscopy, electron imagine = freeze protein, image with electron micsooeps, reconstruct stricture
* channel structure

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25
PDB
standard format sicncetis stoe protien structures atom: N x,y,z
26
levinthals Paradox
proteins have; 10^300 possible conformation -fold in milliseconds - folding guided by energy landsca-pe * otherwise how else doe sit find its right fold in instant --> so thus golding is not random
27
Ion Channel Structural Biology
First ion channel structure 1998, First KV structure 2003, First NaV structure 2011, First human NaV structure 2019, Most human CaV, NaV & KV structures available! 2026
28
De Novo Protein Design
Design of Enzymes (catalysis), Design of Assemblies
29
Rediffusion
rediffusion - diffusional modale -start random structure --> ai refines strutted --stabel proeyin fold emerges system then det * which amino sequence will proceed this stuertcyes
30
Why Target NaV1.7 and NaV1.8?
sensory neurons = pain NAv1.7 --> pNS,s chain sells --> Tax sentive --> set threshed for Action potneitla. firing --> humans with LOF cant feel pain Nav1.8 --> PNS --> txt= resistant --> support rpepeitve firing --> high activation threshold
31
Why Phase II fails so often
Phase 2 --> first time drugs are tested in outings - discover if drug doesn't work - if dose wrong - safety problems
32
pre clinical development
- cell exeoribet -animal models - toxicity Testung
33
structural optimization
- chemist modify structure to improve: -- oral avlaibitly -resistance to b lacunas e - broader bacterial coverage
34
Cinical reasehc an development phases
Phase 1: ( 12-100) --- safety tolerabilty, PK ---effects on biomarkers --- absorbtion and metabolism Phae2: ( 100-300) ---det if drug works --evaluate side effects ---det dose Phase 3: ( 1,000-30,000) -confim efectives -monito rare side effects generate approval data
35
Biomakrers clicnila devleopment
Biomarkes --measuble biological indicators of drug effect --can be used to predict / infer clinal efficacy --validated for effect -- can be tracked early in development
36
Phase 1 study
types of phases 1 studies: --- single dose escalation ---multipel dose escaltion ---drug interaction studies ---prrof of concept Ex: (( adme, bioquevilanve, special pop , safety studies)
37
challenges of PHASE 1
- prediction of human dose -incorporitng flexibly ( we dont knwo what to expect) -msmtn of biomarkers --- can be didifcit ( in healthy volunteers) -- long term effects ( beyond just acute setting)
38
phase 2/3 requirements
1. pivotal proof of efficacy ( rational de for dose) 2. long term clinical safety --> risk benefit 3.drug supply issues -- container stiablily 1 year test 4. safety sees,emt --. chronic toxicology and cargocegneic stud ( 2 yr ) to enter phase 3
39
Entering Phase 3
what we need to knwo to enter phase 3: ---> understanding of product profile ( belief that drug at phase dose can deliver it) --> dose selection -->e enfpdoitn ---> risk benefit ---> safety ALL ABOUT DOSE NO more exploring
40
Phase 3 to filling
Phase III produces the final evidence needed for approval. *provdie full safety and efficacy date data --> for filing -- one dose explores - endpoints pre specified --saftey monitoring --> board study integrity --2 studies run and must be positive -advusory commute rebie 9
41
Clinical Pharmacokinetics
drug concentration vs Time --cmax= peak conc --tmax= time to peak --AUc = total druh exposrue half-life ---HELP DET DOSING SCHUELD
42
modeling and simulation -- used for?
MS: - justify dose adjustment - drug interaction patient population effet -selection of dose
43
Population Pharmocokinetics
PPK links drug exposure: ---> links drug exposure in human --. age, BMI, race, smoke status, food intake, genetic background, drug exposure, kidney function ( why dp these values differ bet patient/ do covartites change drug exposure) * helps predict how difrnt population respond to drugs **intial modes created form phase 1 ---> BC In Phase I studies researchers collect many blood samples from each subject.
44
Physiologically able dphamrokeminte modeling
- mathematical etching - predicts ghwi chemical moves through body --based on biology and kinetic constant
45
What is diabetes
- metabolic disease - hyperglycemia - defects in insulin /secretion/ both -
46
normal blood glucose
80-100 mg/dl 5.5 mm
47
random bllod glucose diabetes
200 mg/dl 11.l mmol/l
48
fasting glucose
126 mg /dl 7 mmil/l
49
abnormal oral glucose
x>above 200 mg /dl (2 hrs post 75g glucose)
50
HbA1
glycated hemoglobin glycation = chemical rxn bonds glucose to proteisn avg glucose over 90 days bc rbc live about 3 months x > 6.5%
51
Complication of. diabetes.
- vascular abnormalities ---- high glucose damage blood vessels ( necrosis of tissue, heart disease, stroke) -Renal damage ---glucso damage glomerular filtration structure -periphernical nerve damage -eye damage
52
Hwo does high glucsoe achieve these effects of complications in DIBATES
1. Glycolysation of proteins -----high glucose causes non enzymatic glycation ---alters protein modification ( ex: glucose + pretein = covalent mod) 2.Reactive oxygen species ---excess glucose metabolism increases --damwges cells 3. Beta cell susceptibility and VESSEL damage : --beta = vulnerable to oxidative stress --progress loss of insulin secretion
53
blood glucose regulation -- When glucose increase
high glucsoe -- b cess activated --> insulin released Insulin acts on: -muscle ( store as glycogen) -fat (store as fat) -liver ( store as glycogen)
54
When glucose dec regulation
glucose decreases -- a cells activated -gluclacog related --- Liver activated ( glycogen to glucose) - releases glucose
55
Insulin signaling via RTK
Inosuin ---------------> RRTK RTK ---------------------> autopjosh ( transauto) IRS protein activate --> PI3K PI3K--------------> AKT AKT-----------------> Glut 4 vesicle glut 4 vesicle ( brought to membrane)---> glucose ----- glucose uptake and suppression in glucnoengensis.
56
Insulin release mechanisms ( start glucose0
1. glucsoe ---> Glut 2 ( transporters) 2. enter beta cell 3. Glucose phosphorylated by ---> GCK 3. Glucose 6 prostate ( now) --> glycolysis 4. pyruvate --> ATp în cytoplasm 5. generate more ATp în mito 6. ATp /adp ration ---> KATP now CLOSES 7.membrane depolarizes (less neg) 8. voltage dep CA 2+ ---> OPEN 9. calcium enters 10. calici triggers insulin granule EXCOTUYSIS 11. other facts amplify insulin releases
57
membrane potential
Na/K = pump maintains gradient ( 3 out 2 K in) glucose uptake -------------- Na+ ----> n cell K+ ---> efflux cell
58
incretins
incretins: -small peptide hormone -secreted from intestine -communicate with beta cell, stomach ,brain two impt ones GIP GLP-1
59
GIP
glucose dependent insulinotropic polypeptide -secreted from: k cell - UPEER intestine function: stimulates insulins secreiiton ( WHEN glucsoe present). * brain, pancreas
60
GLP-1
glucagon like peptide -FROm- proglucagon protein Secreted: L cells, Lower intestine Effects: stomach emptying , appetite regulation * brain, stomach. Pancrea s
61
how do inceptions have their effect
GPCR - Gas couple -Increitns --->GPCR -Gas activated ---> Adenyl cyclase activated - camp made --> active PKA/ EPAC2(
62
what does PKA do
- acts on K (atp) channel ---> close them -acts on voltage gated Ca2+ channels ---> slow down inactivation --acts on Kv channels rectifying --> slows their activation ( prolong AP) -acts on Camp GEFII---> PKA promotes ca2+ release from ER * INC -CA2+ in cell = ATP synthesis ---> inc membrane depolarization ( cdue to closer of KATP) * Ca and CAMP = increases excotytosi of INSULIN.
63
What does EPAC2 do
CAmP GefII -- promote ca2+ releases from ER - inc Ca in cel
64
Type 2 diabetes
Genetic s+ environment -gentic = 50% -beta cell function Insulin resistance --> inc obesity -sednetary lifestyle diet high sugar/fat
65
hwo do people develop type 1 diabetes
Genetics + enviment ( more than half risk) -HLA immune genes: promote autoimmunes dieses -infection ( gastrointestinal( --> triggers immune response which destroys BETA cell
66
type 1 diabetes mechanism
-viral infection--> immune response - immune response --> cells releases cytokines / chemokines -chemokines --> recruit immune cells ( T cells and michrphages) --B cells proteins presented by HLA genes --> immune system misidentifies them as foreign --T cells attack--> B ( beta) cells --Insulitis --> immune cell infiltraion of pancreatic islets -Bcell number decreases damage --> insulin production dec * autoanitbeo = marker of disease ( biomakress). ****** immense cells detsrya beta cells at slow pace takes a while top be diagnose
67
Metformin
hepatic mitochondria = liver DEC GLUcogneogenes MECH: ---metformin---> AMPK activated -AMPK ( metabolic energy sensor when activated signals low energy state) ---> 1. inhibits FBpase (fructose 1,6biphosphate) -no Fbpase = no gluconoegenesis 2. inhibits adenyl cyclase = lower camp 3. inhibit fat synthesis ( promote fat oxidation) = reduce lipid stores ( reduces insulin resistance) 4. activates PDE = lower camp * derive from French Lilac -
68
SGTL2 inhibitor
SGTL2 inhibitor - block glucose reabsorption in KIDNEY ( in kidney there is the ---> proximal convoluted tube ---> an d SGLT2 transproptet) SGTL2 transporter allows glucose t enter renal and enter capillary.
69
sulfonylureas
Sulfonylureas: - act on beta cells - promote---> insulin release ------ MECH -- sulfonylureas bind ----> sur 1 subunit ( of KATP) ---KATP -- artificially close even without glucose. ---insulin secretion inc --> glucose lowered further
70
Incretind medication -- incretin agonists
act on beta cels promote insulin release. injection = bc peptide cant be taken orally ( given tract would digest them) why long life = bc DPP4 nexyem prevents it form being broken down * mimic GLP -1 hormone amp pathway of insulin gas gets
71
GCGR
glucagon receptro --->.
72
Semaglutide
GLP1-R
73
Tirzepatide
GIPR
NPB 107
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