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drug discovery > lecture 4 > Flashcards

lecture 4 Flashcards

1
Q

what is a lead compound

A

a hit compound that has good activity against the chosen target but isnt good enough to be a drug just yet

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2
Q

5 characteristics of a lead compound

A
  • confirmed potency (low ec50)
  • confirmed selectivity
  • desired ADME profile
  • emerging SAR
  • desired safety profiles
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3
Q

what happens in the hit to lead phase

A

u assess several hit clusters to identify 2-3 hit series that have the potential to become leads/drugs

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4
Q

what is in vitro

A

in glass

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5
Q

what is in vivo

A

use of animal models

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6
Q

what is ex vivo

A

post mortem
extraction of organs / cells /
toxicology tissue

test this

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7
Q

what is in silico

A

on the computer

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8
Q

parts of the lead optimisation cycle

A

design: modify the compound

synthesis: making the compound using a computer

evaluate: test the drug (assay the ic50, ec50, ic50 again)

interpret: the data

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9
Q

what does optimisation mean

A

to make smt as perfect as possible

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10
Q

ic50

A

half max inhibitory conc

conc needed to inhibit a bio process by 50%

test of efficacy

reduces binding

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11
Q

ec50

A

half max effective conc

conc of drug needed to get half the response/effect of it

potency of the drug

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12
Q

designing and improving the lead compound involves manipulation of what

A

manipulation of multiple parameters

chemical modifications - changing chemical parameters

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13
Q

how many strategies are there for lead optimisation

A

making the lead compound as perfect as possible

2 strategies : they optimise 2 aspects

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14
Q

what 2 aspects does lead optimisation optimise

A
  • interaction between ligand and biological target
    ( max efficacy and affinity)
  • ligand delivery / access to the target
    ( diff bio environments needs diff ligand characteristics)
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15
Q

different drugs that have different biological targets in diff sections of the body also have

A

different parameters that need to be met in order for them to be successful

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16
Q

what does an oral drug need to be

A
  • lipid soluble to pass the gut bilayer
  • water soluble to pass through the blood stream
  • lipid soluble to pass across the cell membranes
  • then it finally reaches the target
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17
Q

what can be done to optimise a lead compound

A

synthesise a structural variant on the lead compound

structural varient : larger section of dna

this can optimise its properties to become a drug candidate

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18
Q

optimisation of more than one property: ADME

A
  • activity
  • adsorption
  • metabolism
  • excretion
  • toxicity

done in in vitro as its hard to maintain the animals used in in vivo

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19
Q

SAR

A

structure activity relationship

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20
Q

what does the drugs activity depend on

A

the drugs structure

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21
Q

what is included when talking about a drugs structure

A

shape
lack/presence of a functional group

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22
Q

what is included when talking about a drugs properties

A

activity
toxicity
metabolism
formulation
shelf life

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23
Q

what does SAR mean

A

the way in which altering the molecular structure of drugs alters their interaction with a receptor / enzyme

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24
Q

what does sar help with

A

helps guide choice of analogues to synthesise

these are compounds that have the same structure as various parmalogical compounds

aka if ‘x’ needs a drug, sar helps us see that we need drugs similar to ‘y’ to treat ‘x’

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25
Q

what are types of SAR strategies

A
  • removing / altering FG
  • adding new groups
  • changing size + shape
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26
Q

what can a hydroxyl be altered into in SAR strategy of removing/altering FG

A

ester
ether

27
Q

what can a amine be altered to in SAr strategy of removing / alterig FG

A

amide

28
Q

what can a ketone be altered to in SAR strategy of removing/ altering FG

A

alcohol

29
Q

what can an aromatic ring be altered to in SAR strategy of altering/ removing FG

A

cyclohexyl

30
Q

what groups can be added in SAR adding FG group strategy

A

CH3

halogens

alcohols

amidines

amines

guanidines

31
Q

what can be changed to change shape ans size in SAr strategie for changing size + shape

A

change position of substituents

ring system change

change chain length

32
Q

what are bioisosteres

A

groups with similar physical / chemical properties that have similar biological activity

small eg: H + F elements

33
Q

what are isosteres

A

groups with the same amount of valence electrons

34
Q

examples of isosteres

A

CH3
NH2
OH
F

35
Q

what is a TZP

A

THIAZ
DID INE
DIONES

36
Q

what do thiazdidinediones do

A

control diabetes by improving insulin responsiveness of the liver, adipose tissue + skeletal muscle

37
Q

what is similar in all
thiaz did ine diones

A

they all have similar structures

38
Q

parts of the structure of thiaz did ine dione

A

head group

p subs aromatic

linker

hydrophobic / aromatic group

39
Q

how was SAR used in thiaz did ine diones

A

helped make rosiglitazone from ciglitazone

40
Q

the actual ways rosiglitazone is similar to ciglitazone are found in notesss

A
41
Q

what does QSAR stand for

A

quantitative structure activity relationship

42
Q

what is a QSAR

A

a mathematical relationship between activity + physiochemical parameters

43
Q

what is a parameter

A

numbers that represent a molecular property

44
Q

molecular properties that parameters can be used for

A

lipophilicity
shape
e- distribution

45
Q

what is a pharmacophore

A

an abstract description of molecular features that are necessary for molecular recognition of a ligand by a bio molecule

aka an abstract description of molecular features a ligand must have in order for the bio molecule to recognise it

characteristics that show how ur compound will interact with the target

46
Q

what can the pharmacophore model be used for

A

to see how structurally diverse ligands will bind tothe same active site

used to identify novel ligands that could bind to a certain receptor (using de novo design / virtual screening)

47
Q

lipophilicity - molecular parameter can be found using what equation

A

log p =
log ( conc of drug in octanol / conc of drug in aquaeous buffer )

48
Q

what does log p do

A

measures the compounds lipophilicity

49
Q

range of values possible for lipophilicity

A

-6 to 6

50
Q

what is the goal of a lipophilic value

A

0, 1, 2, 3

u dont want either of the 2 extremes

51
Q

if ur drug is found in octanol this meansss

A

its lipophilic

high log p value

52
Q

if ur drug is found inthe aqueous buffer this meansss

A

its hydrophilic

low log p value

53
Q

what can we do in order to make smt more hydrophilic

A

add FG that will make it more water soluble ( OH )

54
Q

what can we do in order to make smt more lipophilic

A

add FG that will make it more lipophilic ( NH2. // NH )

55
Q

examples of size molecular parameters

A

molecular weight
molecular volume
surface area
taft steric parameter ( its size - key for fitting in the enzyme pocket // receptor )

56
Q

electronic parameters example

A

HAMMETT CONSTANTS

measure of the e- withdrawal // e- donation

57
Q

structural parameters example

A
  • number of hydrogen donors / acceptors ( key in SAR + drug molecule determination)
  • number of rotational bonds
58
Q

what is the lipinskis 5 used for

A

its a rule for orally active drugs

predicts if a compound may be ‘drug like’

59
Q

lipinskis rule of 5

A
  • molecular weight < 500
  • no more than 5 H bond donors
  • no more than 10 H bond acceptors
  • partition coefficient, log p < 5
60
Q

what is included in modelling

A
  • 3d QSAR being used to design new molecules without knowing the structures receptor : computer can be used to model new structures into a 3d pharmacophore
  • modelling receptors: generate a 3d model of the receptor based on a 3d pharmacophore and place the amino acid side chains appropriately.
61
Q

what is included in virtual screening

A

pharmacophore matching

docking calculations

62
Q

what is pharmacophore matching

A

where u screen databases (available compounds) for those with the desired pharmacophore

63
Q

what is docking calculations in virtual screening

A

can be made when a receptors structure is known

computer positions ligands in receptor sites

scores ligands according to binding strength

drug discovery (18 decks)

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