lecture 3 Flashcards
what is a hit compound
a molecule/compound which has the desired activity in a compound screen.
it’s activity is confirmed upon retesting
what is hit identification
a process of identifying + delivering a compound with confirmed activity against a biological target
between which processes does hit finding go between
target identification
target validation
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hit - lead
lead optimisation
3 examples of technology that enable HIT identification
- functional assays
- phenotype assays
-Ai
types of functional assays (experiments that dtermine the involvment of proteins in a particular pathway)
- 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
what is high throughput screening
many compounds being tested in an automated fashion for activity as inhibitors (antagonists) or activators (agonists) of a particular biological target.
what is the goal of high throughput screening
screen lots of compounds with diverse chemical structures + identify potential hits
phenotypic assay examples (seeing how small molecules alters the phenotype of a cell in the desired manner)
high content imaging
seeing how the therapeutic interact with cells
AI examples
- virtual, in silico, computational screening, computer aided drug discovery (CADD)
- Ai // logics
techniques that enable hit identification can be run in aaaa
sequence or in parallel for optimum impact
does hit conformation occur before or after hit identification
after
hit confirmation is when
a hit is evaluated
what are 5 ways a hit can be evaluated in hit confirmation
- confirmatory testing
- dose response curves
- secondary screening
- synthetic tractability
- freedom to operate (patent)
what is confirmatory testing in hit confirmation
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)
what is dose curve response in Hit confirmation
a curve that shows how increasing the dose of drug increases the effect of the drug.
parts of the dose response curve
no effect range
range of increasing effect with increasing dose
maximum effect range
what is secondary screening in Hit confirmation
confirmed hits are tested in a functional cellular assay to determine efficacy
what is synthetic tractability in hit confirmation
when medicinal chemists evaluate compounds according to their synthesis feasibility, cost etc
if ur preparation is dangerous or expensive, good luck
what is freedom to operate in hit confirmation
when no one has a patent for the drug already
if they do, u can’t make any money with the drug
what is a ligand
a ligand is a drug or a endogenous molecule
what is a receptor
an enzyme
what is a signal transduction
a response
efficacy definition
ability of the drug-receptor complex to produce a maximum functional response
what does high efficacy correspond to
corresponds to high potency.
if it gives a strong response, it’s very potent
there is a fast response after the drug/ligand binds
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
affinity definition
the ability of the drug to bind to its molecule target
what does high affinity mean
strong binding to a target
relationship between affinity and efficacy
no relationship
one can be low, one can be high
both can be low
both can be high
what is an agonist
a molecule that binds to a receptor
activates it to produce a response
what is an antagonist
a molecule that binds to the receptor and blocks the activation, preventing a response
exp of dose response curve with agonists
higher drug conc = higher response
diff types of agonist in the agonist x antagonist dose response curve
full agonist
partial agonist
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inverse agonist
what is a full agonist
max response
what is a partial agonist
partial response
what is an inverse agonist
negative response
antagonist in agonist x antagonist dose response curve
neutral antagonist
response stays at 0 no matter the conc of drug
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
what is EC50
efficacy conc of 50
conc of drug that gives half the maximum response
what does efficacy conc 50 correspond to
potency
a low EC50 = high potency
lower conc needed to get half the max response
what is IC50
conc of an inhibitor where the response/binding is reduced by half
inhibitor conc 50
what does a low EC50 and IC50 mean in terms of potency
high potency
smaller values are more potent
what 3 parameters is a drugs toxicity based on
CC50
Therapeutic index
safety margin of drug in animal model
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.
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
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)
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
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)
therapeutic index : in vivo
definition
measuring the safety margin of a drug in animal models
therapeutic index in vivo equation
TI= LD50 / ED50
what is LD50 in therapeutic index in vivo
lethal dose 50
dose required to kill 50% of test animals
a high number is wanted
what is ED50 in therapeutic index in in vivo
dose required for efficacy in 50% of animals
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)
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
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
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
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.
what is needed to find a lead compound
3-6 hit compound series are selected and are further explored to identify a lead compound
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
