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drug discovery > lecture 3 > Flashcards

lecture 3 Flashcards

1
Q

what is a hit compound

A

a molecule/compound which has the desired activity in a compound screen.

it’s activity is confirmed upon retesting

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2
Q

what is hit identification

A

a process of identifying + delivering a compound with confirmed activity against a biological target

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3
Q

between which processes does hit finding go between

A

target identification
target validation
XXXXXXXX
hit - lead
lead optimisation

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4
Q

3 examples of technology that enable HIT identification

A
  • functional assays
  • phenotype assays

-Ai

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5
Q

types of functional assays (experiments that dtermine the involvment of proteins in a particular pathway)

A
  • high throughput screening
  • in vitro cell based assays (help mimic complex biological environments to help predict how the compound will act in in vivo)
  • biochemical assays
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6
Q

what is high throughput screening

A

many compounds being tested in an automated fashion for activity as inhibitors (antagonists) or activators (agonists) of a particular biological target.

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7
Q

what is the goal of high throughput screening

A

screen lots of compounds with diverse chemical structures + identify potential hits

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8
Q

phenotypic assay examples (seeing how small molecules alters the phenotype of a cell in the desired manner)

A

high content imaging

seeing how the therapeutic interact with cells

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9
Q

AI examples

A
  • virtual, in silico, computational screening, computer aided drug discovery (CADD)
  • Ai // logics
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10
Q

techniques that enable hit identification can be run in aaaa

A

sequence or in parallel for optimum impact

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11
Q

does hit conformation occur before or after hit identification

A

after

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12
Q

hit confirmation is when

A

a hit is evaluated

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13
Q

what are 5 ways a hit can be evaluated in hit confirmation

A
  • confirmatory testing
  • dose response curves
  • secondary screening
  • synthetic tractability
  • freedom to operate (patent)
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14
Q

what is confirmatory testing in hit confirmation

A

active compounds are retested against the target under the same assay conditions used in High Throughput screening.

makes sure that the hits activity is REPRODUCIBLE (consistent)

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15
Q

what is dose curve response in Hit confirmation

A

a curve that shows how increasing the dose of drug increases the effect of the drug.

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16
Q

parts of the dose response curve

A

no effect range

range of increasing effect with increasing dose

maximum effect range

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17
Q

what is secondary screening in Hit confirmation

A

confirmed hits are tested in a functional cellular assay to determine efficacy

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18
Q

what is synthetic tractability in hit confirmation

A

when medicinal chemists evaluate compounds according to their synthesis feasibility, cost etc

if ur preparation is dangerous or expensive, good luck

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19
Q

what is freedom to operate in hit confirmation

A

when no one has a patent for the drug already

if they do, u can’t make any money with the drug

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20
Q

what is a ligand

A

a ligand is a drug or a endogenous molecule

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21
Q

what is a receptor

A

an enzyme

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22
Q

what is a signal transduction

A

a response

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23
Q

efficacy definition

A

ability of the drug-receptor complex to produce a maximum functional response

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24
Q

what does high efficacy correspond to

A

corresponds to high potency.
if it gives a strong response, it’s very potent

there is a fast response after the drug/ligand binds

25
Q

what does low efficacy correspond to

A

low efficacy corresponds to low potency

a small/ slow response when the drug binds the the receptor means the drug isn’t potent

26
Q

affinity definition

A

the ability of the drug to bind to its molecule target

27
Q

what does high affinity mean

A

strong binding to a target

28
Q

relationship between affinity and efficacy

A

no relationship

one can be low, one can be high
both can be low
both can be high

29
Q

what is an agonist

A

a molecule that binds to a receptor
activates it to produce a response

30
Q

what is an antagonist

A

a molecule that binds to the receptor and blocks the activation, preventing a response

31
Q

exp of dose response curve with agonists

A

higher drug conc = higher response

32
Q

diff types of agonist in the agonist x antagonist dose response curve

A

full agonist
partial agonist
xxxxxxxxxxxx
inverse agonist

33
Q

what is a full agonist

A

max response

34
Q

what is a partial agonist

A

partial response

35
Q

what is an inverse agonist

A

negative response

36
Q

antagonist in agonist x antagonist dose response curve

A

neutral antagonist

response stays at 0 no matter the conc of drug

37
Q

if ur drug is a neutral antagonist or a inverse agonist, how will increasing its conc affect the response

A

it won’t
the response will always be small

38
Q

what is EC50

A

efficacy conc of 50

conc of drug that gives half the maximum response

39
Q

what does efficacy conc 50 correspond to

A

potency

a low EC50 = high potency

lower conc needed to get half the max response

40
Q

what is IC50

A

conc of an inhibitor where the response/binding is reduced by half

inhibitor conc 50

41
Q

what does a low EC50 and IC50 mean in terms of potency

A

high potency

smaller values are more potent

42
Q

what 3 parameters is a drugs toxicity based on

A

CC50

Therapeutic index

safety margin of drug in animal model

43
Q

what is CC50 in toxicity

A

cytotoxic conc 50
conc of drug that reduces the number of viable cells by 50% compared to the control
measures toxicity.

44
Q

what value of CC50 in toxicity is needed for the drug to be safe

A

a high value

a high conc should kill 50% of cells,, not a low conc

45
Q

what is the therapeutic index in toxicity

A

range of doses at which a medication is effective without unacceptable adverse effects.

TI: CC50 / IC50 (in vitro)

46
Q

what therapeutic index value is needed for a drug to be safe

A

u want a high therapeutic index value

meaning the CC50 value must be large

47
Q

can a low therapeutic index be acceptable

A

yes!!
may be accepted to treat a life threatening disease that has a limited number of treatment options (chemo and cancer)

48
Q

therapeutic index : in vivo
definition

A

measuring the safety margin of a drug in animal models

49
Q

therapeutic index in vivo equation

A

TI= LD50 / ED50

50
Q

what is LD50 in therapeutic index in vivo

A

lethal dose 50

dose required to kill 50% of test animals

a high number is wanted

51
Q

what is ED50 in therapeutic index in in vivo

A

dose required for efficacy in 50% of animals

52
Q

what is hit expansion

A

hit ranking and clustering

confirmed hits are ranked according to the various hit conformation experiments

confirmatory tests, dr curves, secondary screening, synthetic tractability, freedom to operate)

53
Q

what characteristics do ideal compound clusters possess

A
  • high affinity towards the target
  • selectivity against other targets
  • significant efficacy in a cellular assay
  • drug likeness
  • low to moderate binding to human serum albumin
  • low interference with p450 + p-glycoproteins
  • low cytotoxicity
  • metabolic stability
  • high cell membrane solubility
  • sufficient water solubility
  • synthetic tractability
  • patentability
54
Q

why are good hits better

A

theres an increased likelihood that theyll lead to a successful drug discovery

takes less years for them to become a drug candidate

55
Q

why are bad hits bad

A

they have a higher chance of failing then becoming successful drugs

takes more years and screening for them to enter lead generation

56
Q

what is a lead compound

A

compound with a structure that has some activity against thr chosen target
but isn’t good enough to be a drug itself just yet.

57
Q

what is needed to find a lead compound

A

3-6 hit compound series are selected and are further explored to identify a lead compound

58
Q

what is the hit -> lead phase

A

when several hits clusters are assessed to identify 2-3 hit series that have the best potential to develop into drug like leads

drug discovery (18 decks)

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