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drug discovery > lecture 4 > Flashcards

lecture 4 Flashcards

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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
what are types of SAR strategies
- removing / altering FG - adding new groups - changing size + shape
26
what can a hydroxyl be altered into in SAR strategy of removing/altering FG
ester ether
27
what can a amine be altered to in SAr strategy of removing / alterig FG
amide
28
what can a ketone be altered to in SAR strategy of removing/ altering FG
alcohol
29
what can an aromatic ring be altered to in SAR strategy of altering/ removing FG
cyclohexyl
30
what groups can be added in SAR adding FG group strategy
CH3 halogens alcohols amidines amines guanidines
31
what can be changed to change shape ans size in SAr strategie for changing size + shape
change position of substituents ring system change change chain length
32
what are bioisosteres
groups with similar physical / chemical properties that have similar biological activity small eg: H + F elements
33
what are isosteres
groups with the same amount of valence electrons
34
examples of isosteres
CH3 NH2 OH F
35
what is a TZP
THIAZ DID INE DIONES
36
what do thiazdidinediones do
control diabetes by improving insulin responsiveness of the liver, adipose tissue + skeletal muscle
37
what is similar in all thiaz did ine diones
they all have similar structures
38
parts of the structure of thiaz did ine dione
head group p subs aromatic linker hydrophobic / aromatic group
39
how was SAR used in thiaz did ine diones
helped make rosiglitazone from ciglitazone
40
the actual ways rosiglitazone is similar to ciglitazone are found in notesss
41
what does QSAR stand for
quantitative structure activity relationship
42
what is a QSAR
a mathematical relationship between activity + physiochemical parameters
43
what is a parameter
numbers that represent a molecular property
44
molecular properties that parameters can be used for
lipophilicity shape e- distribution
45
what is a pharmacophore
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
what can the pharmacophore model be used for
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
lipophilicity - molecular parameter can be found using what equation
log p = log ( conc of drug in octanol / conc of drug in aquaeous buffer )
48
what does log p do
measures the compounds lipophilicity
49
range of values possible for lipophilicity
-6 to 6
50
what is the goal of a lipophilic value
0, 1, 2, 3 u dont want either of the 2 extremes
51
if ur drug is found in octanol this meansss
its lipophilic high log p value
52
if ur drug is found inthe aqueous buffer this meansss
its hydrophilic low log p value
53
what can we do in order to make smt more hydrophilic
add FG that will make it more water soluble ( OH )
54
what can we do in order to make smt more lipophilic
add FG that will make it more lipophilic ( NH2. // NH )
55
examples of size molecular parameters
molecular weight molecular volume surface area taft steric parameter ( its size - key for fitting in the enzyme pocket // receptor )
56
electronic parameters example
HAMMETT CONSTANTS measure of the e- withdrawal // e- donation
57
structural parameters example
- number of hydrogen donors / acceptors ( key in SAR + drug molecule determination) - number of rotational bonds
58
what is the lipinskis 5 used for
its a rule for orally active drugs predicts if a compound may be 'drug like'
59
lipinskis rule of 5
- molecular weight < 500 - no more than 5 H bond donors - no more than 10 H bond acceptors - partition coefficient, log p < 5
60
what is included in modelling
- 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
what is included in virtual screening
pharmacophore matching docking calculations
62
what is pharmacophore matching
where u screen databases (available compounds) for those with the desired pharmacophore
63
what is docking calculations in virtual screening
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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