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drug discovery > lecture 5 > Flashcards

lecture 5 Flashcards

1
Q

lectures before this one focused on processes in what stage

A

processes in the early stage of development

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2
Q

lecture 5 focuses on what stage

A

the preclinical stage of drug discovery

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3
Q

what does preclinical mean

A

before humans

pre = before
clinical = humans

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4
Q

what are the preclinical test research activities

aka what is tested in preclinical studies

A
  • toxicology
  • pharmacodynamics
  • pharmacokinetics
  • optimisation of drug delivery systems
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5
Q

what is pharmacodynamics

A

what the drug does to the body

if it goes to the right place

biochemical effect of the drug

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6
Q

what is pharmacokinetics

A

how the body handles the drug

what the body does to the drug

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7
Q

what is optimisation of drug delivery systems

A

how the drug will be delivered

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8
Q

why are iterations carried out. why is it repeated

A
  • to reduce toxicity
  • to improve pharmacokinetic performance
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9
Q

what is the goal of preclinical drug development

A
  • an optimised compound is found + becomes a potential drug
  • its ready for clinical trials
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10
Q

what must the drug respect in order to go from preclinical to clinical trials

A

it has to follow good GLP

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11
Q

what is GLP

A

good laboratory practice

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12
Q

what does good laboratory practice ensure

A

ensures that the proper quality system + ethical considerations are established

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13
Q

what 2 things occur in lead compound optimisation

A
  • structural varient is synthesised on the lead compound
  • more than one property is optimised (ADME)
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14
Q

what does synthesising a structural varient on the lead compound do

A

it optimises its properties to become a drug candidate

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15
Q

what must happen to go from prescription to patient health

A

ADME

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16
Q

what does ADME stand for

A

activity
adsorption
metabolism
excretion
toxicity

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17
Q

ADME stands for descriptors that quantify a drug : which are

A
  • entering the body
  • moving around the body
  • changing within the body
  • leaving the body
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18
Q

overtime ADME has diversified according to the

A

needs of others

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19
Q

what mechanisms is ADME used to describe

A
  • crossing the gut wall
  • movement between compartments
  • mechanism of metabolism
  • excretion / elimination
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20
Q

what are the 2 ADME stages

A

in vitro ADME.
in vivo ADME

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21
Q

why is in vitro ADME a thing

A

it uses cell cultures in order to estimate how a new product will react

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22
Q

why is in vivo ADME used

A

used to validate in vitro ADME

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23
Q

how do cells transport molecules

A

transcellular
paracellular

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24
Q

what is transcellular transport

A

active + passive

through the cell membrane

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25
Q

what is paracellular transport

A

transport between cells

h2o, ions, small solutes, molecules

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26
Q

why is cell transport important

A

biological targets are usually found in cells

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27
Q

what is drug permeability important in

A

oral drug absorption

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28
Q

what are oral drug absorption dependent on

A

its passive permeability

the possibility that a transport protein will uptake the drug

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29
Q

2 assays to study permeability

A

PAMPA
Caco-2 cell assay

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30
Q

what does PAMPA stand for as an assay of permeability

A

parallel artificial membrane permeability assays

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31
Q

is PAMPA in vitro or in vivo

A

in vitro
transcellular transportation
through cell membranes

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32
Q

describe PAMPA permeability assay

A

test compound in buffer in the DONOR WELL

lipid membrane that mimics a cell membrane

RECEIVER WELL this is where the drug is transported into

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33
Q

what is the goal of PAMPA

A

to see if the drug is transported across the cell membrane or if it neeeds a transport protein

we can tell

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34
Q

what is the Caco-2 cell assay testing

A

testing paracellular transport,, using a real cell monolayer to see if the drug can be transported between cells

uses a real cellular model

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35
Q

stages of Caco-2 cell assay

A

see if the dye passes through the monolayer from the aptical to basolateral chamber

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36
Q

what is an advantage of Caco-2 against pampa

A

Caco-2 uses a real cell system better as it uses a real. cullular model (cell monolayer)

37
Q

Papp is the

A

apparent permeability coefficient

38
Q

equation for Papp

A

dQ(conc in basal chamber) /dTime

x 1/Area x C0 (initial conc)

39
Q

what measures plasma binding + drug distribution

A

in vitro binding assays

measure if the drug binds to proteins

40
Q

in vivo assays that measure drug binding to proteins

A

PPB BTB BPP

plasma protein binding
brain tissue binding
blood plasma partitioning

41
Q

in the body, what equilibrium is available to drugs

A

being bound + binding to smt or being free

42
Q

what happens when a drug is bound to something

A

it cannot bind to the target
it isnt effective

43
Q

what happens when the drug is free to move

A

it can bind to the target
it can be effective

44
Q

what things in the body could a drug bind to

A

proteins
lipids
tissues

45
Q

what normally metabolises small molecules

A

CYP P450
cytochrome p450

46
Q

what are the cytochrome p450

A

family of enzymes located in the HEPTATIC ENDOPLASMIC RETICULUM

47
Q

what are the 2 stages of drug metabolism

A

phase 1
phase 2

48
Q

what is the main goal for both phases of metabolism

A

to increase water solubility of the drug to facilitate excretion via sweat/urine

49
Q

phase 1 description of metabolism

A

CYP chemically modifies the drug

they add OH to make the molecule more polar (SAR)

add more polar FG to change the way its metabolised

50
Q

what is phase 2 of metabolism

A

conjugation of modified scaffold to polar molecules (sugar)

they conjugate the molecuke in order to make it more polar so it can be eliminated rapidly in bile/urine

51
Q

what are the phase 2 metabolism conjugation examples

A

glucuronidation
sulphation
amino acids
acetylation
methylation

52
Q

what is glucuronidation

A

attaching a drug to an oxidised glucose in order to increase its polarity to be rapidly eliminated

53
Q

what is sulphation

A

adding a sulfo group to a drug to increase its polarity in order to be eliminated quicker

54
Q

what is a sulfo group

A

think sulfuric acid

HSO3

55
Q

difference between a sulfated drug and a normal drug

A

a sulfated drug is more polar and therefore easily eliminated

56
Q

what technique can be used to improve metabolism of drugs

A

SAR
structure activity relationship

57
Q

how is SAR generally used in order to improve drug metabolism

A

moving// substituting certain functional groups in order to block certain processes // strengthen bonds

58
Q

SAR + improving metabolism:: how do we block aromatic hydroxylation

A

substitute a phenyl ring with a para-chlorine group to deactivate the ring

59
Q

SAR + improving metabolism:: how do we block metabolism

A

adding certain FG
making bonds stronger by replacing Hydrogens with Fluorines

stronger bonds need more time to be broken

60
Q

what does changing the structure of a compound do

A

changes the SAR
changes the metabolism
changes the amount of doses needed

61
Q

do we watch a drug that needs lots of frequent doses or one that doesnt need as much doses

A

we want a drug which needs a little amount of doses

62
Q

in order for a drug to have a small number of doses,, what must SAR do

A

it must decrease the drugs metabolism,, allowing it to be present in the body for longer periods of time

63
Q

what does a short half life mean

A

it means the drug spends less time in the body

more doses will be needed to maintain a high concentration of it

64
Q

SAR tries to give drugs aaa

A

longer half life
more time in body
less doses needed

65
Q

what organ is the major site of drug metabolism in the body

A

the liver

66
Q

what happens in the liver

A

metabolism of most drugs

67
Q

what are 50% of marketed drugs eliminated by

A

the heptatic mediated metabolism

HMM

68
Q

what is the HMM

A

heptatic mediated metabolism

how 50% of marketed drugs are metabolised

69
Q

what are liver microsomes

A

subcellular fractions that cotain membrane bound drug metabolising enzymes like CYP

70
Q

how are subcellular fractions obtaines

A

liver microsomes are obtained via cell fractionation

71
Q

name a membrane bound, drug metabolising enzyme in the liver

A

CYP

72
Q

what can microsomes be used to determine

A

used to determine the in vivo intrinsic clearance of a compound

73
Q

intrinsic clearence equation

A

Clint = Vmax (max rate of enzymatic reaction) /// Km (enzyme dissociation constant)

74
Q

what does intrinsic clearence tell us,, Clint

A

how efficient an enzyme is at metabolising the drug

– faster Vmax,, rate of enzyymatic reation = more efficient metabolism

75
Q

high intrinsic clearence akaaa

A

high clearence category
aka fast rate of metabolism
aka efficient metabolism

76
Q

name 2 toxicity tests

A

hERG

mitochondrial toxicity

77
Q

what is hERG

A

a gene
human ether a go go gene
inhibiting the hERG gene leads to negative effects on the heart (cardiotoxic effects)

role in cardiac repolarisation

we want to test that our drug does not interfere wth hERG

78
Q

what is mitochondrial toxicity + what tissues does it effect

A

metabolic disease
affects active tissues/ tissues with more energy consumption:

skeletal muscles, cardiac + neurological tissues

79
Q

what cell is the source of atp

A

the mitochondria

80
Q

steps of drug ingestion to drug excretion

A

drug is ingested
drug undergoes body processes

drug is either modified or unchanged

drug is excreted

81
Q

name 2 types of drug excretion

A

active excretion

passive excretion

82
Q

how does passive excretion occur

A

kidney filtration

83
Q

how does active excretion occur

A

using proteins such as kidney transporters

84
Q

active excretion uses transporters and there are many in vitro methods to study these transporters

A

vesicular transport is an assay method,

recombinant cell lines,

bidirectional transport assays in polarised monolayers

  • identifies cytotoxic compounds
85
Q

what is in vitro adme used for

A

to provide insight into how a cell responds to a new drug in an isolated + controlled environment

86
Q

what are the 3 pros of in vitro adme

A
  • cheaper than using animal models
  • faster than in vivo assays
  • easily automated using organ on a chip
87
Q

what are the 2 conc of in vitro adme

A
  • physiologically limited (only a few cells can be tested at a time)
  • hard to tranlate into in vivo results
88
Q

why are there new trends in adme research

A
  • there was ethical concerns over the use of animals
  • interspecies pathophysiological differences between animal models and humans
89
Q

what is a new trend in adme research

A
  • use of 3d cell models instead of an animal model

still a work in progress tho

drug discovery (18 decks)

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