H2L Flashcards by Kim Grace

involves testing the compound library (or a part of
it) to find out molecules that act on the desired target
(i.e. the hits)

HIT GENERATION

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Enforce attrition to immediately discard
anything that has no chance of being active

HIT GENERATION

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make sure that the hits or other
compounds are more competitive; eliminate
compounds that are not competitive

Attrition

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Screening process here is STRICT

HIT GENERATION

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rampant and
should be eliminated

Nuisance molecules

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Hits must be validated, otherwise they are
merely called

actives

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Actives that look like they’re working but are not

FALSE POSITIVES

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Positive result but the hit is not interacting with the
target

FALSE POSITIVES

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Common types of false positives:

Promiscuous binders
Pan-assay Interference Compounds
(PAINs)

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actives that actually
bind the desired target, but target many other
things too

Promiscuous binders

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Usually lead to unwanted toxicity or side
effects

Promiscuous binders

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Entertain everything and tend to trigger
toxic effect

Promiscuous binders

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actives that don’t bind to the desired
target at ALL

Pan-assay Interference Compounds
(PAINs)

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Just gives positive results to any assay
thrown at it

Pan-assay Interference Compounds
(PAINs)

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Interfere with different assay

Pan-assay Interference Compounds
(PAINs)

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It is a __________ if an active binds to an unwanted target, or does not bind to a real target.

red flag

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-need to use primary and secondary screening
methods

HIT VALIDATION

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use of counterscreens (secondary screening
method) which serve as a sort of trap

HIT VALIDATION

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T/F: A REAL HIT MUST NOT PASS THE
COUNTERSCREEN

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Hits should test _________ in counterscreen

negative

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If a test compound gives a positive
result for both the screen and
counterscreen, it is “_________” from
being a hit

disqualified

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In Hit Validation, If hit disqualification does not give sufficient
confidence, the next resort is use of ____________

biophysical
techniques

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A lead should

-have confirmed activity
-show evidence of desired selectivity
-have activity in cellular systems
-have stability in biologic systems
-Free from toxicity alerts

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T/F: Even if a true hit is potent, it may be toxic or have
poor ADME (pharmacokinetic profile)

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assures that millions of dollars won’t be wasted developing a drug that will fail in clinical trials or be withdrawn from the market

Discharging risk ASAP

a ‘fail fast, fail cheap’ strategy

Discharging risk ASAP

Goal: Discharge risk as much and as early as possible

LEAD GENERATION

options in choosing the starting point

A: get existing drug B: New Drug/Indication

Researches can opt to use existing compounds in the human body

A: get existing drug

Use of existing molecules leads to _____________

me-too drugs

can often offer improvements over the original drug (‘me better’ drugs) as their selling point

me-too drugs

T/F: Me-too drugs can have challenges in drug registration by the FDA because the activity of the drug you are trying to register is the same as the one in the market,

Me-too drugs can have challenges in drug registration by the FDA because the activity of the drug you are trying to register is the same as the one in the market,

Serotonin

quaternary ammonium compound; template used to produce Cevemaline (dry mouth treatment)

Acetylcholine

derivative of Nebivolol (antihypertensive medication)

Norepinephrine

Drug is already developed but different activity is highlighted

OPTION B: NEW DRUG/INDICATION

Drug repurposing/repositioning SOSA

OPTION B: NEW DRUG/INDICATION

same drug, different activity

Drug repurposing/repositioning

same drug, but converted to an analogue, different activity

SOSA

modified drug molecule to further enhance the activity of the drug

Analogue

example of SOSA

Isoniazid

T/F: much time and money is saved when existing structures are used

Often follows forward approach to discovery

NATURAL

these are done to find actives, then followed by determination of mechanism of action and drug targets

Screens

Skips the need for getting many reagents and reacting them by organic synthesis

NATURAL

are very complex compounds, and thus, original most of the time

Natural products

Much more challenging than synthetic route in terms of compound isolation

NATURAL

Only limited number of unique compounds

NATURAL

“Back to Zero”

NATURAL

may be toxic

NATURAL

The Philippine drug discovery and development program

TUKLAS LUNAS

Employed in both forward and reverse approaches of discovery

synthetic compound libraries can be tested immediately

forward method

libraries can be designed to obey predictive data that may come from previous CADD data

reverse method

Easier isolation, and skips the horrors of endless extraction and chromatography

synthetic

Can deliver up to thousands or millions of compounds

synthetic

Provides limited access to chemical space and requires more reaction steps

synthetic

produces mixtures of different compounds within each reaction vessel

Combinatorial synthesis

combinatorial synthesis is more random, and is more applicable for ________

hit-to-lead generation

produce a single product in each vessel

Parallel synthesis

More focused, and is more applicable for lead optimization

Parallel synthesis

Parallel and combinatorial methods are used not just for small molecule synthesis, but also

peptide synthesis

Both methods generally involve the use of

solid phase techniques

-A cross-linked insoluble polymeric support -An anchor or linker covalently linked to the resin -A bond linking the substrate to the linker -A means of cleaving

Essential requirements for solid phase synthesis:

The techniques of solid phase synthesis have been used to produce ______ quantities of compounds from a particular reaction sequence

large

Best to synthesize spider-like molecules than tadpole-like molecules

SYNTHETIC

Chances of success are greater if the “arms” are ____________ to allow more thorough exploration of chemical space

evenly spread

only explore chemical space on a limited area, and wastes the chance of seeing what can happen if other regions in space are filled

Tadpole-like molecules

Mixtures of compounds are produced in each vessel, allowing production of up to millions of novel structures in a span of time that only a few compounds are usually made with conventional labwork

COMBINATORIAL SYNTHESIS

In combinatorial synthesis, each reaction vessel is not purified, and is tested for biological activity as a ______

whole

Messy and expensive due to the need for many reagents

COMBINATORIAL SYNTHESIS

Can produce millions of structures

COMBINATORIAL SYNTHESIS

Sometimes called concentric synthesis

PARALLEL

Carried out in a series of wells such that each well contains a single product

PARALLEL

Reagents are added one by one without jumbling everything

PARALLEL

Lesser products made, but purer in quality

PARALLEL

Often used for lead optimization rather than generation

PARALLEL

NMR, XRC and SPR are used in this option

A: in vitro screening

Mistakes of HTS can be checked by _______ to ensure that the compounds concerned are binding in the correct binding site

NMR

Molecular recognition events are simulated and input as very large virtual compound libraries to be screened in silico

OPTION B: VIRTUAL SCREENING

Biological screening accounts for about 15% of the total expenditures of an industry

OPTION B: VIRTUAL SCREENING

if there is no information on activity yet

Prospective

if there are already known drugs

Retrospective

a classic method of testing thousands of compounds against the target, if the target protein is already well-known and has an existing X-ray structure

Molecular docking

with its intense computations, cannot be routinely done to thousands of compounds, and has to wait when leads are narrowed down during optimization

Molecular dynamics,

Pharmacophore models are useful especially when full elucidation of the drug target structure lags behind the results of screening experiments

OPTION B: VIRTUAL SCREENING (LBDD)

Once the pharmacophore model is constructed, ___________ can be done

virtual screening

no or little information is provided about the mechanism of action, BUT it does give direct results

HTS

not as convincing as HTS, but provides useful information about the mechanism of action