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Drug Discovery > May > Flashcards

May Flashcards

(96 cards)

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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
stain for gel electrophoresis
ethidium bromide intercalates between base pairs in double helix fluoresces under UV light
26
ColE1 origin of replication
used to tell the bacteria to replicate the plasmid
27
antibiotic resistance gene
used so only the bacteria with the insert will survive
28
site directed mutagenesis
changing a protein and observing the change in pharmacology | used for interpreting and understanding the molecular nature of the drug-target interaction
29
pharmacogenetics
genetic variations revealed by clinically used drugs | how genes affects body's reactions to drugs
30
pharmacogenomics
Development of new drugs from the discovery of new genes, possibility of creating personalised drugs for individuals based on their own genetic makeup
31
Succinylcholine sensitivity
neuromuscular blocking agent used in surgery apnoea- won't be able to breathe for themselves prolonged paralysis sensitivity in autosomal recessive
32
tandem repeat
small section of genome repeated | e.g. Huntington's disease- expansion of tandem repeat
33
copy number variation
several copies of a large part of the genome e.g. 3/4 copies of a gene
34
SNP
single nucleotide alteration 1- change nucleic acid and amino acid 2- change in nucleic acid but no change in amino acid
35
next generation sequencing
sequencing the whole genome
36
epigenetic marks
changes within the genome that affect gene expression but are not based on changes in the DNA sequence
37
absorption
movement of drug from site of action to systemic circulation
38
bioavailability
measurement of rate and extent to which drug reaches systemic circulation applies to all routes of administration
39
chloroquine
antimalarial becomes sequestered in fat tissue needs to be taken for a long time for it to reach therapeutic concentration
40
phase 1 reactions
oxidation, reduction or hydrolysis reactions
41
phase 2 reactions
conjugation- something added so it is more likely to be eliminated
42
clearance
measurement of drug elimination from the plasma
43
propranolol
fused aromatic rings all in 1 plane | can slot into a narrow binding site because planar
44
benzene
bond angles 120
45
acetylcholine
planar at one end and tetrahedral at the other rotatable carbon-carbon bond in the middle positively charged at physiological pH
46
cyclohexane
``` 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
trap a conformation
1- improve efficacy | 2- understand what conformation is to improve pharmacophore
48
hydroxyl group
not an ionisable group- doesn't leave a negative charge 109 forms hydrogen bonds
49
carbonyl group
planar polar- O drags electrons from C hydrogen bonds can be accepted
50
carboxyl group
can ionise | is negatively charged
51
amide group
don't ionise polar lots of hydrogen bonds
52
peptide bond
doesn't rotate partial double bond fixed in trans formation
53
malignant hyperthermia
heterogenous halogenated GA- cause massive release of calcium from ryanodine receptors -->massive amount of energy within muscles autosomal dominant
54
induced pluripotent stem cells
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
debiquisone
used as a probe for CYP2D6 activity
56
4 categories of adverse effects
1- mechanism related 2-off target- acts on different receptor 3-dose related toxicity 4- idiosyncratic- unrelated to MOA
57
features of an effective clinical trial
informed consent clear exclusion and inclusion criteria a control double blind
58
NME
new molecular entity
59
lead optimisation
improve pharmacokinetics, without losing efficacy
60
paracellular diffusion
compound has to cross the epithelial cell | from GI tract into hepatic portal vein
61
first pass metabolism
occurs in the intestinal cell wall | cells are able to perform metabolic reactions
62
hepatic first pass metabolism
occurs in the liver | extensively metabolises drugs- CYP enzymes
63
MDCK MDR1 monolayers
used to estimate P glycoprotein susceptibility | canine kidney cell lines from distal tubule or collecting duct of the nephron
64
why can muscarine only bind to GPCR
has a less flexible ring so cannot form the shape that ACh does when binding to the nicotinic receptor conformation is important
65
inverse agonist
force receptors into the inactive state
66
pA2
concentration of antagonist that requires a 2-fold increase in agonist concentration to regain original response level
67
scintillation proximity assay
transparent base with scintillants radiologand bound receptors will separate from free radioactive bound with produce light when close to the scintillant
68
fluorescence polarisation
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
lanthanide chelates
long fluorescence decay - eliminates background fluorescence - gives time to ready assay
70
FRET
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
TR-FRET
uses lanthanide chelates
72
LANCE
biotin and streptavidin used to stick things together | used in biotech
73
Reporter Assays
activate GPCR- downstream signalling produce cell lines that have reporter genes -->may require hours of receptor activation
74
IP3 assay
Gq pathway lithium results in the breakdown of IP3 and buildup of IP1 activate receptor- increase in IP1 time resolved fluorescence
75
Ca2+
FURA2- fluorescent Ca2+ indicator when bound to calcium- 340nm not bound- 380nm 340/380 ratio- accurate measurement of intracellular Ca2+
76
advantages of x-ray crystallography
better resolution | not limited by protein size
77
disadvantages of x-ray crystallography
need to make crystals | -->this is difficult for membrane proteins
78
advantages of NMR
don't need crystals | can study dynamics
79
disadvantages of NMR
limited by protein size- <35 kDa
80
NMR
pure protein in solution work out distances between certain atoms find a solution which matches the distances
81
AUG
start codon 10 bases on 3' side of RBS ribosome binds to RBS then locates AUG
82
operator sequence
sequence between promotor and genes transcribed
83
affinity chromatography
something that binds specifically to the protein of interest
84
string of histidine residues
will bind to nickel ions | use imidazole to wash off- similar structure to histidine
85
disadvantages of using bacteria plasmids
no post-translational modification | disulphide bonds do not form
86
Ura3
allows yeast to grow without uracil
87
G-C
3 hydrogen bonds
88
DNA ligase
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
transformation
rupturing bacterial cell wall to encourage them to take up plasmid DNA
90
site directed mutagenesis steps
1- denaturation- 95 2- annealing- cooled in the presence of primer 3- extension- DNApol uses DNTPs to make complementary chain
91
dpn1
four base pairs destroys DNA that is methylated -->original DNA made in vivo
92
transfection
introduction of foreign genetic material into eukaryotic cell
93
electroporation
disrupt bilayer by producing an electric field close by
94
lipofection
using DNA with cationic lipids
95
Cmax
maximum concentration that a drug acheives
96
Tmax
time at which Cmax is achieved

Drug Discovery (2 decks)

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