ppt on qsar studies

1. QUANTITATIVE STRUCTURE-
ACTIVITY RELATIONSHIPS
(QSAR -STUDIES)
By
VIJAYA LAKSHMI NANDIKATTI,
M.PHARM(Ph.D)

2. HISTORY OF QSAR
1868, D. Mendeleev – The Periodic Table of Elements
1868, A. Crum-Brown and T.R. Fraser – formulated a suggestion
that physiological activity of molecules depends on their
constitution:
Activity = F(structure)
They studied a series of quaternized strychnine derivatives,
some of which possess activity similar to curare in paralyzing
muscle.
1869, B.J. Richardson – narcotic effect of primary alcohols varies
in proportion to their molecular weights.

3. 1893, C. Richet has shown that toxicities of some simple
organic compounds (ethers, alcohols, ketones) were
inversely related to their solubility in water.
1899, H. Meyer and 1901, E. Overton have found
variation of the potencies of narcotic compounds with
LogP.
1904, J. Traube found a linear relation between narcosis
and surface tension.

4. 1937, L.P. Hammett studied chemical reactivity of
substituted benzenes:
Hammett equation,
Linear Free Energy Relationship (LFER)
1939, J. Fergusson formulated a concept linking
narcotic activity, logP and thermodynamics.
1952- 1956, R.W. Taft devised a procedure for
separating polar, steric and resonance effects.

5. 1964, C. Hansch and T. Fujita: the biologist’s Hammett
equation.
1964, Free and Wilson, QSAR on fragments.
1970s – 1980s – development of 2D QSAR
(descriptors, mathematical formalism).
1980s – 1990s, development of 3D QSAR
(pharmacophores, CoMFA, docking).
1990s – present, virtual screening.

6. 1934 - Hammett
R H CH3 OCH3 F Cl NO2
ortho 6.27 12.3 8.06 54.1 11.4 671
meta 6.27 5.35 8.17 13.6 14.8 32.1
para 6.27 4.24 3.38 7.22 10.5 37.0

7. STERIC EFFECTS
Taft quantified the steric (spatial) effects using the hydrolysis of esters:
Here, the size of R affects the rate of reaction by blocking nucleophilic attack by
water.
In this case, the steric effects were quantified by the Taft parameter Es:
k is the rate constant for ester hydrolysis. This expression is analogous
to the Hammett equation.

8. Es Values for Various Substituents
H Me Pr t-Bu F Cl Br OH SH NO2 C6H5 CN NH2
0.0 -1.24 -1.60 -2.78 -0.46 -0.97 -1.16 -0.55 -1.07 -2.52 -3.82 -0.51 -0.61
Compare some extreme values:
H - 0.00 the reference substituent in the Taft equation
Me - -1.24: little steric resistance to hydrolysis
t-Bu - -2.78 : large resistance to hydrolysis
Note: H is usually used as the reference substituent (Es(0)), but
sometimes when another group, such as methyl (Me) is used as
the reference, as in the chemical equation above, the value
becomes 1.24.

9. STERIC EFFECTS
Es may be used in other chemical reactions and to explain
biological activities, for example the hydrolysis of inhibitors of
acetylcholine esterase.
Organophosphates must be hydrolysed to be active and it is
observed that their biological activity is directly related to the Taft
steric parameter ES for the substituent R by the equation:

10. Octanol/water partition coefficient
Usually, logP instead of P is used
logP > 0, the compound prefers hydrophobic (unpolar)
media
logP > 0, the compound prefers polar media

11. HANSCH ANALYSIS
Biological Activity = f (EL, ST, HPh) + constant
Biological Activity = log1/C
C, drug concentration causes EC50, GI50, etc.
EL (electronic descriptor):
 Hammett constant ( m,  p, p
0, p
+, p
-, R, F )
HPh (hydrophobicity descriptor):
 hydrophobic subst. constant, log P octanol/water
partition coeff.
ST (steric descriptor): Taft steric constant
log1/C = a ( log P )2 + b log P +  + Es + C

12. HANSCH ANALYSIS
Biological Activity = f (Physicochemical properties ) +
constant
Physicochemical properties can
be broadly classiied into three
general types:
Electronic
Steric
Hydrophobic

13. Merits of Hansch analysis
Corelative activities with pysicochemicalparameters
 Outside predictions are possible.