5 | Compound Preparation and H2L Generation

Question 1

molecules with POTENTIAL to be selected as leads

Answer 1

Hit

Question 2

generated during the initial screening process

Answer 2

Hit

Question 3

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

Answer 3

True (lead generation = lead finding)

Question 4

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

Answer 4

Lead

Question 5

Leads eventually become ____________________________

Answer 5

drug candidates

Question 6

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

Answer 6

optimized

Question 7

Goal of hit generation

Answer 7

enforce attrition

Question 8

Why is there a need to enforce attrition?

Answer 8

to immediately discard anything that has no chance of being active

Question 9

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

Answer 9

False (hit generation)

Question 10

make sure that the hits or other compounds are more competitive

Answer 10

attrition

Question 11

Attrition eliminate compounds that are _________________

Answer 11

not competitive

Question 12

Screening process in hit generation is ___________

Answer 12

strict

Question 13

actives that look like they’re WORKING BUT ARE NOT

Answer 13

false positives

Question 14

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

Answer 14

True

Question 15

common types of false positives

Answer 15

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

Question 16

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

Answer 16

promiscuous binders

Question 17

Promiscuous binders usually lead to unwanted ___________ or ____________

Answer 17

toxicity or side effects

Question 18

Promiscuous binders entertain everything and tend to _______________________

Answer 18

trigger toxic effect

Question 19

PAINs stand for

Answer 19

Pan-assay interference compounds

Question 20

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

Answer 20

PAINs

Question 21

gives positive results to ANY ASSAY thrown at it

Answer 21

PAINs

Question 22

interfere with different assay

Answer 22

PAINs

Question 23

Identify the active type

presence of real target binding with no unwanted targets

Answer 23

hits

Question 24

Identify the active type

presence of real target binding and unwanted targets

Answer 24

promiscuous

Question 25

Identify the active type absence of real target binding with no unwanted targets

Answer 25

PAINs

Question 26

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

Answer 26

True

Question 27

a hit plus other requirements

Answer 27

lead

Question 28

hit requirement

Answer 28

must have confirmed activity

Question 29

lead requirements

Answer 29

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

Question 30

type of synthetic approaches

Answer 30

1. combinatorial synthesis 2. parallel synthesis

Question 31

produces MIXTURES of different compounds within each reaction vessel

Answer 31

combinatorial synthesis

Question 32

combinatorial synthesis is ______________ and __________________ for H2L generation

Answer 32

more random and more applicable

Question 33

initial step prior to parallel synthesis

Answer 33

combinatorial synthesis

Question 34

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

Answer 34

False (increase reagents, more compounds)

Question 35

produce a SINGLE product in each vessel

Answer 35

parallel synthesis

Question 36

Parallel synthesis is more focused and is more applicable for ________________________

Answer 36

lead optimization

Question 37

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

Answer 37

combinatorial and parallel synthesis

Question 38

combinatorial and parallel synthesis generally involve the use of ______________________________

Answer 38

solid phase techniques

Question 39

carry out synthesis on solid beads rather than in solution

Answer 39

solid phase techniques

Question 40

essential requirements for solid phase synthesis

Answer 40

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

Question 41

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

Answer 41

cross-linked insoluble polymeric support

Question 42

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

Answer 42

anchor (anchor or linker covalently linked to the resin)

Question 43

stable to the reaction conditions used in the synthesis

Answer 43

bond linking the substrate to the linker

Question 44

Essential requirements for solid phase synthesis a means of cleaving the product of the _____________________________

Answer 44

intermediate from the linker

Question 45

two types of scaffolds

Answer 45

1. spider 2. tadpole

Question 46

spider or tadpole: which is better

Answer 46

spider

Question 47

why is spider scaffold better than the tadpole scaffold?

Answer 47

has more branches, results to more possible reactions

Question 48

the branches "_______________" contain functional group

Answer 48

scaffold

Question 49

spider and tadpole scaffolds processes are involved in _______________________

Answer 49

molecular docking

Question 50

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

Answer 50

combinatorial synthesis

Question 51

96 well plate

Answer 51

before 2000's

Question 52

high throughput meaning testing of thousands of compounds PER WEEK

Answer 52

before 2000's

Question 53

384 or 1536-well plates

Answer 53

last 2 decades

Question 54

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

Answer 54

last 2 decades

Question 55

docking and pharmacophore modeling use depending on information available

Answer 55

1. prospective 2. retrospective

Question 56

if there is NO INFORMATION yet

Answer 56

prospective

Question 57

CADD use in prospective study

Answer 57

predict novel compounds that may work

Question 58

if there are already KNOWN DRUGS

Answer 58

retrospective

Question 59

CADD use in retrospective study

Answer 59

trace reasons why structure of drugs worked

Question 60

mechanism: less detailed translatability: more confidence

Answer 60

HTS (in vitro)

Question 61

mechanism: more detailed translatability: less confidence

Answer 61

VS (in silico)

Question 62

HTS stands for

Answer 62

high-throughput screening

Question 63

VS stands for

Answer 63

virtual screening