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PHA6125 Drug Discovery and Development > 5 | Compound Preparation and H2L Generation > Flashcards

5 | Compound Preparation and H2L Generation Flashcards

1
Q

molecules with POTENTIAL to be selected as leads

A

Hit

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2
Q

generated during the initial screening process

A

Hit

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3
Q

T/F: only the MOST ACTIVE hits are chosen during LEAD GENERATION to become leads

A

True (lead generation = lead finding)

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4
Q

selected hits with potency, safety, and other qualities wanted in a drug

A

Lead

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5
Q

Leads eventually become ____________________________

A

drug candidates

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6
Q

Lead needs to be further _________________ to proceed with clinical development/study

A

optimized

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7
Q

Goal of hit generation

A

enforce attrition

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8
Q

Why is there a need to enforce attrition?

A

to immediately discard anything that has no chance of being active

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9
Q

T/F: From millions or thousands, LEAD GENERATION should end only with several HUNDRED COMPOUNDS

A

False (hit generation)

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10
Q

make sure that the hits or other compounds are more competitive

A

attrition

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11
Q

Attrition eliminate compounds that are _________________

A

not competitive

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12
Q

Screening process in hit generation is ___________

A

strict

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13
Q

actives that look like they’re WORKING BUT ARE NOT

A

false positives

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14
Q

T/F: Flase positives yield positive results but the hit is not interacting with the target

A

True

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15
Q

common types of false positives

A
  1. promiscuous binders
  2. pan-assay interference compounds (PAINs)
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16
Q

actives that actually BIND THE DESIRED TARGET, but TARGET OTHERS too

A

promiscuous binders

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17
Q

Promiscuous binders usually lead to unwanted ___________ or ____________

A

toxicity or side effects

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18
Q

Promiscuous binders entertain everything and tend to _______________________

A

trigger toxic effect

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19
Q

PAINs stand for

A

Pan-assay interference compounds

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20
Q

actives that DON’T BIND TO THE DESIRED TARGET at all

A

PAINs

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21
Q

gives positive results to ANY ASSAY thrown at it

A

PAINs

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22
Q

interfere with different assay

A

PAINs

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23
Q

Identify the active type

presence of real target binding with no unwanted targets

A

hits

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24
Q

Identify the active type

presence of real target binding and unwanted targets

A

promiscuous

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25
Q

Identify the active type

absence of real target binding with no unwanted targets

A

PAINs

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26
Q

T/F: Hit should ONLY INTERACT with the REAL TARGET

A

True

27
Q

a hit plus other requirements

A

lead

28
Q

hit requirement

A

must have confirmed activity

29
Q

lead requirements

A
  1. confirmed activity
  2. evidence of desired selectivity
  3. activity in cellular systems
  4. stability in biologic systems
  5. free from toxicity alerts
30
Q

type of synthetic approaches

A
  1. combinatorial synthesis
  2. parallel synthesis
31
Q

produces MIXTURES of different compounds within each reaction vessel

A

combinatorial synthesis

32
Q

combinatorial synthesis is ______________ and __________________ for H2L generation

A

more random and more applicable

33
Q

initial step prior to parallel synthesis

A

combinatorial synthesis

34
Q

T/F: In combinatorial synthesis, INCREASE in REAGENTS may produce LESSER COMPOUNDS

A

False (increase reagents, more compounds)

35
Q

produce a SINGLE product in each vessel

A

parallel synthesis

36
Q

Parallel synthesis is more focused and is more applicable for ________________________

A

lead optimization

37
Q

methods used for small molecule synthesis and peptide synthesis (e.g., insulin, enoxaparin)

A

combinatorial and parallel synthesis

38
Q

combinatorial and parallel synthesis generally involve the use of ______________________________

A

solid phase techniques

39
Q

carry out synthesis on solid beads rather than in solution

A

solid phase techniques

40
Q

essential requirements for solid phase synthesis

A
  1. cross-linked insoluble polymeric support
  2. anchor or linker covalently linked to the resin
  3. bond linking the substrate to the linker
  4. means of cleaving
41
Q

inert to the synthetic conditions (e.g., resin bead)

A

cross-linked insoluble polymeric support

42
Q

has a reactive functional group that can be used to attach a substrate

A

anchor (anchor or linker covalently linked to the resin)

43
Q

stable to the reaction conditions used in the synthesis

A

bond linking the substrate to the linker

44
Q

Essential requirements for solid phase synthesis

a means of cleaving the product of the _____________________________

A

intermediate from the linker

45
Q

two types of scaffolds

A
  1. spider
  2. tadpole
46
Q

spider or tadpole: which is better

A

spider

47
Q

why is spider scaffold better than the tadpole scaffold?

A

has more branches, results to more possible reactions

48
Q

the branches “_______________” contain functional group

A

scaffold

49
Q

spider and tadpole scaffolds processes are involved in _______________________

A

molecular docking

50
Q

mixtures of compounds are produced in each vessel, allowing production of up to millions of novel structures

A

combinatorial synthesis

51
Q

96 well plate

A

before 2000’s

52
Q

high throughput meaning testing of thousands of compounds PER WEEK

A

before 2000’s

53
Q

384 or 1536-well plates

A

last 2 decades

54
Q

well plates used can handle thousands of compounds PER DAY which is the modern definition of high throughput

A

last 2 decades

55
Q

docking and pharmacophore modeling use depending on information available

A
  1. prospective
  2. retrospective
56
Q

if there is NO INFORMATION yet

A

prospective

57
Q

CADD use in prospective study

A

predict novel compounds that may work

58
Q

if there are already KNOWN DRUGS

A

retrospective

59
Q

CADD use in retrospective study

A

trace reasons why structure of drugs worked

60
Q

mechanism: less detailed
translatability: more confidence

A

HTS (in vitro)

61
Q

mechanism: more detailed
translatability: less confidence

A

VS (in silico)

62
Q

HTS stands for

A

high-throughput screening

63
Q

VS stands for

A

virtual screening

PHA6125 Drug Discovery and Development (3 decks)

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