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QSAR (quantitative structure-activity relationship) (image (statistical…
QSAR (quantitative structure-activity relationship)
what is QSAR?
mathematical eq. tht quantifies the relationship between the physicochemical properties of a drug & its biological activity
why QSAR?
bcs impossible to buat analogue of every substituent/ combination of substituent
therefore, perlu tau which substituent we want to synthesis
advantage of QSAR
kurangkan no. of analogue to synthesis
lead utk further development
criteria QSAR
structurally -related
act on same target
same of mechanism of action
correct testing procedure
eg: in vitro test on isolated enzyme. in vivo not valid sbb
linear regression analysis using least square method
best line
sum of sqared vertical value from line is minimum
correlation coefficient (r^2)>0.8
r>0.9
good fit
equation is valid
standard deviation (s) compare dengan s of experiment
statistical test (eg Fishers F-test) utk tengok significant of partition coefficient (p)
p<0.05 -->significant
p- ratio of conc. between 2 immiscible liq when equilibrium is achieved
P-partition coefficient (physicochemical properties)
C-conc. of drug perlu utk ada biological activity (1/C-biological properties)
common physicochemical propeties studied by QSAR
hydrophobicity
cross membrane
how easily drug bind to albumin
interaction w receptor
partition coefficent, P= conc. of drug in octanol / conc of drug in water mixture
P 'knot'- optimum partition coefficient utk biological activity
<log P 'knot': hydrophobic (suka air), increase anaesthetic activity, enter membrane
log P 'knot': terbalik
p 'knot'- optimum partition coefficient utk achieve biological activity
substituent hydrophobicity constant, π= logP'x'- log P'h'
electronic effect
affect polarity & ionisation
affect permeability
σ= logK'x' - log K'h' (Hammett eq)
K- equlibrium/ dissociation constant
σ'p'>σ'm'
Electron withdraw at para ada inductively & resonance
electron withdraw dekat meta ada inductive saja
σ'p'<σ'm'
electron donating dekat para ada resonance
electron donating dekat meta ada inductive
limitation of Hammett eq
x boleh utk ortho position
hanya utk yg ada aromatic ring
depends on EWG/ EDG
