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Drug Discovery > May > Flashcards

May Flashcards

1
Q

Translational Chemistry

A

when a particular substance exhibits biological activity

starts with the chemistry

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2
Q

Translational Biology/ Medicine

A

observation of biological property/ concept- manipulated for therapeutic benefit
based on a specific clinical observation

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3
Q

Substance for translational chemistry

A

d-tubocurarine
antagonist at nicotinic ACh receptors
used in open chest surgery to paralyse the diaphragm

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4
Q

drug found from library based

A

warfarin- lead to tipranavir

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5
Q

drug found in ligand-based

A

LNFPI (peptide) lead to saquinivir

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6
Q

drug found in structure-based

A

Ritanovir- symmetrical

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7
Q

pharmacophore

A

part of molecular structure that is responsible for biological/ pharmacological interaction

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8
Q

approaches for ligand based discovery

A
  • based on a known ligand (endogenous based design)
  • based on an initial hit (prototype based design)
  • based on a known drug (analogue based design)
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9
Q

how to increase diversity of a library

A
  • collect from natural sources
  • traditional medicines (Chinese)
  • combinatatorial chemistry- computer slightly changes a molecule so related but different
  • in silicon library screening
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10
Q

lipinskis rule of 5

A
  • molecular mass <500 Da
  • LogP <5
  • <5 hydrogen bond donors
  • sum of Ns and Os less than 10
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11
Q

Caco-2 monolayers

A

see if it can cross the surface of the GIT
Caco-2 cells mimic enterocytes
form gap junctions

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12
Q

Hepatic microsomal CYP

A

tests metabolism- phase 1 reactions

endosomes are homogenised and form microsomes which contain CP450 enzymes

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13
Q

Hepatic Culture

A

see if liver cells metabolise compounds
phase 2 reactions
how much is being absorbed and any conjugates produced

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14
Q

recombinant processes

A

manipulate the processes of transcription, translation and replication to produce enough protein to carry out screens

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15
Q

Intron

A

non-coding bit of DNA

removed during post-transcriptional modification by splicing

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16
Q

polyadenylation

A

long tail of A’s which are important for stability of RNA

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17
Q

promotor

A

signal that the following regions need to be transcribed

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18
Q

cDNA

A

made in vitro from mRNA from isolated cells and expresses the target protein
contains no introns
made using reverse transcriptase

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19
Q

multiple cloning site

A

has unique restriction sites so the rest of the plasmid will be left untouched
has symmetry so is rare
restriction enzymes- cleave phosphodiester bond- cut the covalent bond in the backbone

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20
Q

EcoR1

A

creates 5’ sticky end

retains a phosphate group

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21
Q

Pst1

A

creates 3’ sticky end

the ends have an OH- group

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22
Q

EcoRV

A

creates blunt ends

less useful as cuts right in the middle

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23
Q

alkaline phosphatase

A

removes the 5’ end so the plasmid cannot re-anneal

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24
Q

T4PNK

A

phosphorylates the 5’ end

important for when insert is synthesised in PCR

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25
Q

stain for gel electrophoresis

A

ethidium bromide
intercalates between base pairs in double helix
fluoresces under UV light

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26
Q

ColE1 origin of replication

A

used to tell the bacteria to replicate the plasmid

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27
Q

antibiotic resistance gene

A

used so only the bacteria with the insert will survive

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28
Q

site directed mutagenesis

A

changing a protein and observing the change in pharmacology

used for interpreting and understanding the molecular nature of the drug-target interaction

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29
Q

pharmacogenetics

A

genetic variations revealed by clinically used drugs

how genes affects body’s reactions to drugs

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30
Q

pharmacogenomics

A

Development of new drugs from the discovery of new genes, possibility of creating personalised drugs for individuals based on their own genetic makeup

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31
Q

Succinylcholine sensitivity

A

neuromuscular blocking agent used in surgery
apnoea- won’t be able to breathe for themselves
prolonged paralysis
sensitivity in autosomal recessive

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32
Q

tandem repeat

A

small section of genome repeated

e.g. Huntington’s disease- expansion of tandem repeat

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33
Q

copy number variation

A

several copies of a large part of the genome e.g. 3/4 copies of a gene

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34
Q

SNP

A

single nucleotide alteration
1- change nucleic acid and amino acid
2- change in nucleic acid but no change in amino acid

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35
Q

next generation sequencing

A

sequencing the whole genome

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36
Q

epigenetic marks

A

changes within the genome that affect gene expression but are not based on changes in the DNA sequence

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37
Q

absorption

A

movement of drug from site of action to systemic circulation

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38
Q

bioavailability

A

measurement of rate and extent to which drug reaches systemic circulation
applies to all routes of administration

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39
Q

chloroquine

A

antimalarial
becomes sequestered in fat tissue
needs to be taken for a long time for it to reach therapeutic concentration

40
Q

phase 1 reactions

A

oxidation, reduction or hydrolysis reactions

41
Q

phase 2 reactions

A

conjugation- something added so it is more likely to be eliminated

42
Q

clearance

A

measurement of drug elimination from the plasma

43
Q

propranolol

A

fused aromatic rings all in 1 plane

can slot into a narrow binding site because planar

44
Q

benzene

A

bond angles 120

45
Q

acetylcholine

A

planar at one end and tetrahedral at the other
rotatable carbon-carbon bond in the middle
positively charged at physiological pH

46
Q

cyclohexane

A 
all tetrahedral- 109
the ring traps the bonds from rotating
can form 2 conformations
1- both ends up= more stable- methyl groups separated maximally
2- one end up and the other down- boat
47
Q

trap a conformation

A

1- improve efficacy

2- understand what conformation is to improve pharmacophore

48
Q

hydroxyl group

A

not an ionisable group- doesn’t leave a negative charge
109
forms hydrogen bonds

49
Q

carbonyl group

A

planar
polar- O drags electrons from C
hydrogen bonds can be accepted

50
Q

carboxyl group

A

can ionise

is negatively charged

51
Q

amide group

A

don’t ionise
polar
lots of hydrogen bonds

52
Q

peptide bond

A

doesn’t rotate
partial double bond
fixed in trans formation

53
Q

malignant hyperthermia

A

heterogenous
halogenated GA- cause massive release of calcium from ryanodine receptors
–>massive amount of energy within muscles
autosomal dominant

54
Q

induced pluripotent stem cells

A

converting skin cell and covert them back into adult stem cell
reset chromatin and put in other transcription factors to wipe the cell memory

55
Q

debiquisone

A

used as a probe for CYP2D6 activity

56
Q

4 categories of adverse effects

A

1- mechanism related
2-off target- acts on different receptor
3-dose related toxicity
4- idiosyncratic- unrelated to MOA

57
Q

features of an effective clinical trial

A

informed consent
clear exclusion and inclusion criteria
a control
double blind

58
Q

NME

A

new molecular entity

59
Q

lead optimisation

A

improve pharmacokinetics, without losing efficacy

60
Q

paracellular diffusion

A

compound has to cross the epithelial cell

from GI tract into hepatic portal vein

61
Q

first pass metabolism

A

occurs in the intestinal cell wall

cells are able to perform metabolic reactions

62
Q

hepatic first pass metabolism

A

occurs in the liver

extensively metabolises drugs- CYP enzymes

63
Q

MDCK MDR1 monolayers

A

used to estimate P glycoprotein susceptibility

canine kidney cell lines from distal tubule or collecting duct of the nephron

64
Q

why can muscarine only bind to GPCR

A

has a less flexible ring so cannot form the shape that ACh does when binding to the nicotinic receptor
conformation is important

65
Q

inverse agonist

A

force receptors into the inactive state

66
Q

pA2

A

concentration of antagonist that requires a 2-fold increase in agonist concentration to regain original response level

67
Q

scintillation proximity assay

A

transparent base with scintillants
radiologand bound receptors will separate from free
radioactive bound with produce light when close to the scintillant

68
Q

fluorescence polarisation

A

fluorescent molecules excited with plane-polarised light will re-emit at a fixed plane
large molecules rotate slowly- planes of light will be similar to initial excitation
used to quantify binding

69
Q

lanthanide chelates

A

long fluorescence decay

  • eliminates background fluorescence
  • gives time to ready assay
70
Q

FRET

A

excite the ligand- will release energy at a particular wavelength
if interacting with receptor- energy will be accepted and will fluoresce giving a FRET signal
if they do not interact- will have an emission at a different wavelength

71
Q

TR-FRET

A

uses lanthanide chelates

72
Q

LANCE

A

biotin and streptavidin used to stick things together

used in biotech

73
Q

Reporter Assays

A

activate GPCR- downstream signalling
produce cell lines that have reporter genes
–>may require hours of receptor activation

74
Q

IP3 assay

A

Gq pathway
lithium results in the breakdown of IP3 and buildup of IP1
activate receptor- increase in IP1
time resolved fluorescence

75
Q

Ca2+

A

FURA2- fluorescent Ca2+ indicator
when bound to calcium- 340nm
not bound- 380nm
340/380 ratio- accurate measurement of intracellular Ca2+

76
Q

advantages of x-ray crystallography

A

better resolution

not limited by protein size

77
Q

disadvantages of x-ray crystallography

A

need to make crystals

–>this is difficult for membrane proteins

78
Q

advantages of NMR

A

don’t need crystals

can study dynamics

79
Q

disadvantages of NMR

A

limited by protein size- <35 kDa

80
Q

NMR

A

pure protein in solution
work out distances between certain atoms
find a solution which matches the distances

81
Q

AUG

A

start codon
10 bases on 3’ side of RBS
ribosome binds to RBS then locates AUG

82
Q

operator sequence

A

sequence between promotor and genes transcribed

83
Q

affinity chromatography

A

something that binds specifically to the protein of interest

84
Q

string of histidine residues

A

will bind to nickel ions

use imidazole to wash off- similar structure to histidine

85
Q

disadvantages of using bacteria plasmids

A

no post-translational modification

disulphide bonds do not form

86
Q

Ura3

A

allows yeast to grow without uracil

87
Q

G-C

A

3 hydrogen bonds

88
Q

DNA ligase

A

forms new phosphodiester bonds between phosphate and 3’ OH group
can add adaptors to cDNA inserts if they don’t have the right ends
once annealed, can be used again

89
Q

transformation

A

rupturing bacterial cell wall to encourage them to take up plasmid DNA

90
Q

site directed mutagenesis steps

A

1- denaturation- 95
2- annealing- cooled in the presence of primer
3- extension- DNApol uses DNTPs to make complementary chain

91
Q

dpn1

A

four base pairs
destroys DNA that is methylated
–>original DNA made in vivo

92
Q

transfection

A

introduction of foreign genetic material into eukaryotic cell

93
Q

electroporation

A

disrupt bilayer by producing an electric field close by

94
Q

lipofection

A

using DNA with cationic lipids

95
Q

Cmax

A

maximum concentration that a drug acheives

96
Q

Tmax

A

time at which Cmax is achieved

Drug Discovery (2 decks)

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