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drug discovery > lecture 3 > Flashcards

lecture 3 Flashcards

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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

Study These Flashcards
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
what does low efficacy correspond to
low efficacy corresponds to low potency a small/ slow response when the drug binds the the receptor means the drug isn’t potent
26
affinity definition
the ability of the drug to bind to its molecule target
27
what does high affinity mean
strong binding to a target
28
relationship between affinity and efficacy
no relationship one can be low, one can be high both can be low both can be high
29
what is an agonist
a molecule that binds to a receptor activates it to produce a response
30
what is an antagonist
a molecule that binds to the receptor and blocks the activation, preventing a response
31
exp of dose response curve with agonists
higher drug conc = higher response
32
diff types of agonist in the agonist x antagonist dose response curve
full agonist partial agonist xxxxxxxxxxxx inverse agonist
33
what is a full agonist
max response
34
what is a partial agonist
partial response
35
what is an inverse agonist
negative response
36
antagonist in agonist x antagonist dose response curve
neutral antagonist response stays at 0 no matter the conc of drug
37
if ur drug is a neutral antagonist or a inverse agonist, how will increasing its conc affect the response
it won’t the response will always be small
38
what is EC50
efficacy conc of 50 conc of drug that gives half the maximum response
39
what does efficacy conc 50 correspond to
potency a low EC50 = high potency lower conc needed to get half the max response
40
what is IC50
conc of an inhibitor where the response/binding is reduced by half inhibitor conc 50
41
what does a low EC50 and IC50 mean in terms of potency
high potency smaller values are more potent
42
what 3 parameters is a drugs toxicity based on
CC50 Therapeutic index safety margin of drug in animal model
43
what is CC50 in toxicity
cytotoxic conc 50 conc of drug that reduces the number of viable cells by 50% compared to the control measures toxicity.
44
what value of CC50 in toxicity is needed for the drug to be safe
a high value a high conc should kill 50% of cells,, not a low conc
45
what is the therapeutic index in toxicity
range of doses at which a medication is effective without unacceptable adverse effects. TI: CC50 / IC50 (in vitro)
46
what therapeutic index value is needed for a drug to be safe
u want a high therapeutic index value meaning the CC50 value must be large
47
can a low therapeutic index be acceptable
yes!! may be accepted to treat a life threatening disease that has a limited number of treatment options (chemo and cancer)
48
therapeutic index : in vivo definition
measuring the safety margin of a drug in animal models
49
therapeutic index in vivo equation
TI= LD50 / ED50
50
what is LD50 in therapeutic index in vivo
lethal dose 50 dose required to kill 50% of test animals a high number is wanted
51
what is ED50 in therapeutic index in in vivo
dose required for efficacy in 50% of animals
52
what is hit expansion
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
what characteristics do ideal compound clusters possess
- 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
why are good hits better
theres an increased likelihood that theyll lead to a successful drug discovery takes less years for them to become a drug candidate
55
why are bad hits bad
they have a higher chance of failing then becoming successful drugs takes more years and screening for them to enter lead generation
56
what is a lead compound
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
what is needed to find a lead compound
3-6 hit compound series are selected and are further explored to identify a lead compound
58
what is the hit -> lead phase
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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