lecture 4 Flashcards
what is a lead compound
a hit compound that has good activity against the chosen target but isnt good enough to be a drug just yet
5 characteristics of a lead compound
- confirmed potency (low ec50)
- confirmed selectivity
- desired ADME profile
- emerging SAR
- desired safety profiles
what happens in the hit to lead phase
u assess several hit clusters to identify 2-3 hit series that have the potential to become leads/drugs
what is in vitro
in glass
what is in vivo
use of animal models
what is ex vivo
post mortem
extraction of organs / cells /
toxicology tissue
test this
what is in silico
on the computer
parts of the lead optimisation cycle
design: modify the compound
synthesis: making the compound using a computer
evaluate: test the drug (assay the ic50, ec50, ic50 again)
interpret: the data
what does optimisation mean
to make smt as perfect as possible
ic50
half max inhibitory conc
conc needed to inhibit a bio process by 50%
test of efficacy
reduces binding
ec50
half max effective conc
conc of drug needed to get half the response/effect of it
potency of the drug
designing and improving the lead compound involves manipulation of what
manipulation of multiple parameters
chemical modifications - changing chemical parameters
how many strategies are there for lead optimisation
making the lead compound as perfect as possible
2 strategies : they optimise 2 aspects
what 2 aspects does lead optimisation optimise
- interaction between ligand and biological target
( max efficacy and affinity) - ligand delivery / access to the target
( diff bio environments needs diff ligand characteristics)
different drugs that have different biological targets in diff sections of the body also have
different parameters that need to be met in order for them to be successful
what does an oral drug need to be
- 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
what can be done to optimise a lead compound
synthesise a structural variant on the lead compound
structural varient : larger section of dna
this can optimise its properties to become a drug candidate
optimisation of more than one property: ADME
- activity
- adsorption
- metabolism
- excretion
- toxicity
done in in vitro as its hard to maintain the animals used in in vivo
SAR
structure activity relationship
what does the drugs activity depend on
the drugs structure
what is included when talking about a drugs structure
shape
lack/presence of a functional group
what is included when talking about a drugs properties
activity
toxicity
metabolism
formulation
shelf life
what does SAR mean
the way in which altering the molecular structure of drugs alters their interaction with a receptor / enzyme
what does sar help with
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’
what are types of SAR strategies
- removing / altering FG
- adding new groups
- changing size + shape
what can a hydroxyl be altered into in SAR strategy of removing/altering FG
ester
ether
what can a amine be altered to in SAr strategy of removing / alterig FG
amide
what can a ketone be altered to in SAR strategy of removing/ altering FG
alcohol
what can an aromatic ring be altered to in SAR strategy of altering/ removing FG
cyclohexyl
what groups can be added in SAR adding FG group strategy
CH3
halogens
alcohols
amidines
amines
guanidines
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
what are bioisosteres
groups with similar physical / chemical properties that have similar biological activity
small eg: H + F elements
what are isosteres
groups with the same amount of valence electrons
examples of isosteres
CH3
NH2
OH
F
what is a TZP
THIAZ
DID INE
DIONES
what do thiazdidinediones do
control diabetes by improving insulin responsiveness of the liver, adipose tissue + skeletal muscle
what is similar in all
thiaz did ine diones
they all have similar structures
parts of the structure of thiaz did ine dione
head group
p subs aromatic
linker
hydrophobic / aromatic group
how was SAR used in thiaz did ine diones
helped make rosiglitazone from ciglitazone
the actual ways rosiglitazone is similar to ciglitazone are found in notesss
what does QSAR stand for
quantitative structure activity relationship
what is a QSAR
a mathematical relationship between activity + physiochemical parameters
what is a parameter
numbers that represent a molecular property
molecular properties that parameters can be used for
lipophilicity
shape
e- distribution
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
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)
lipophilicity - molecular parameter can be found using what equation
log p =
log ( conc of drug in octanol / conc of drug in aquaeous buffer )
what does log p do
measures the compounds lipophilicity
range of values possible for lipophilicity
-6 to 6
what is the goal of a lipophilic value
0, 1, 2, 3
u dont want either of the 2 extremes
if ur drug is found in octanol this meansss
its lipophilic
high log p value
if ur drug is found inthe aqueous buffer this meansss
its hydrophilic
low log p value
what can we do in order to make smt more hydrophilic
add FG that will make it more water soluble ( OH )
what can we do in order to make smt more lipophilic
add FG that will make it more lipophilic ( NH2. // NH )
examples of size molecular parameters
molecular weight
molecular volume
surface area
taft steric parameter ( its size - key for fitting in the enzyme pocket // receptor )
electronic parameters example
HAMMETT CONSTANTS
measure of the e- withdrawal // e- donation
structural parameters example
- number of hydrogen donors / acceptors ( key in SAR + drug molecule determination)
- number of rotational bonds
what is the lipinskis 5 used for
its a rule for orally active drugs
predicts if a compound may be ‘drug like’
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
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.
what is included in virtual screening
pharmacophore matching
docking calculations
what is pharmacophore matching
where u screen databases (available compounds) for those with the desired pharmacophore
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
