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Quantitative Structure-Activity Relationship (1. Partition Coefficient (P)…
Quantitative Structure-Activity Relationship
1. Partition Coefficient (P)
:check:
concentration in n-octanol/concentration in aqueous phase
greater the P, the higher the affinity for organic phase
Linear equation: log(1/c) = k1logP +k2
Regression constant >0.95 - indicates that P is the factor that affects the binding of compound to the receptor
If plotted a large range - parabolic equation will be obtained
P0 (P knot) - optimum P for maximum biological activity
Parabolic equation: log(1/C)=-k1(logP)2 + k2(logP) +
k3
2. Lipophilic Substituent Constant (π)
:<3:
Applicable to substituent only
Represent the contribution any substituent/functional group makes towards the partition coefficient
π =logPX - logPH ,
where PX and PH are the partition coefficients of the
monosubstituted derivative and the standard compound
respectively
Positive
value - higher
lipophilicity
than hydrogen
Can replace P - only when we are
comparing a series of analogues in which only the
substituents are different
Electronic Parameters -
Hammett's constant (σ)
:red_flag:
Depends on EWG or EDG on
aromatic ring
Positive
value -
EWG
Also depends on ortho,meta or para substitution
Meta
- Inductive effect - positive
Para
-
Resonance/mesomeric effect
- negative
Not applicable to ortho - subject to other factors such as steric hindrance, intermolecular H-bonding etc.
Steric parameter -
Taft Steric Parameter (Es)
:lock:
Standard model used: hydrolysis of methyl ethanoate
5. Hansch analysis
:checkered_flag:
Combine P, electronic distribution and steric parameter
log(1/C) =
k1(partition parameter) + k2(electronic parameter) + k3(steric
parameter) + k4
Value of constant indicates the
level of importance it plays in the mechanism of the drug binding
need not necessarily combine all factors
for maximum activity - both π and σ must be of
opposite sign
Can be quadratic or cubic
If regression value <0.9, indicates that the parameters used to derive may be irrelevant to the mechanism
Biological activity of a compound depends on
its ability to reach and bind to target drug
Nature of the mechanism for the drug
Predict the activity of unsynthesised analogue
If values obtained from Hansch analysis are vastly different from the observed values (from conducting experiment) - influenced by factors that are not included in the equation
Increase accuracy - sufficient sample numbers -
minimum number is 5x
, where x is the number of
parameters used to determine the relationship
6. Craig plot
:tada:
two dimensional plot of one parameter against another parameter
Four sections
- used with Hansch analysis
Highest activity
- lower right-hand quadrant
(2nd quadrant)
+ve π and -ve σ
7. Topliss Decision Tree
:star:
To produce a series of analogues
Limitation:
lead compound must contain
aromatic ring
relied on π and σ values and to a lesser
extent Es values
refer to lecture notes on how to use it