Sent to CCL by: Andreas Klamt [klamt[*]
cosmologic.de]
Hi All,
let me put my 5 cents into the game:
We have done quantum calculations for the heterocyclic ring,
with just a methyl group, since electronically the remainder
of the compound should have almost no influence on the
heterocycle.
DFT/COSMO-RS calculations prove the neutral species
SMILES:CC1C(=O)[NH]C(=O)S1 of the Pioglitazone heterocycle to
be favored by 11.3 kcal/mol compared to all other neutral
species of the heterocycle, which means that there is no other
relvant neutral form.
We find with COSMOtherm that the pka of the heterocycle is
6.55, i.e. at pH=7 it should be deprotonated with about 25%.
Since the pka of the conj. acid of the pyridine ring according
to COSMOtherm (we calculated diethylpyridine) is ~5.6 there
should be ~10% in the zwitterionic form.
It will be hard to decide this finally, unless someone
measures it, but we are quite confident to be qualitatively
right here, because the energy differences for the tautomers
should not have more than 5 kcal/mol erro, as we learned in in
the SAMPL2 tautomer contest:
see Andreas Klamt and Michael Diedenhofen, Some conclusions
regarding the predictions of tautomeric equilibria in solution
based on the SAMPL2 challenge,
http://www.springerlink.com/content/l577667th758n6h1/
Andreas
Hi All,
Using MarvinSketch v5.3.3 (ChemAxon software), the
predicted pKa value
of the acidic hydrogen on the thiazolidinedione ring of
pioglitazone is
4.57 (see attached "Figure_1.gif"). Therefore, the
predominant species
at pH 7.0 predicted by MarvinSketch is the one depicted in
"Figure_2.gif". The different tautomeric forms predicted
by MarvinSketch
are shown in "Figure_3.gif".
Can anyone explain where these predictions come from, and
if they are
correct?
Thanks,
Nancy
On Mon, Jan 10, 2011 at 4:16 AM, Gabriele Cruciani
gabri(0)chemiome.chm.unipg.it
<http://chemiome.chm.unipg.it>
<http://chemiome.chm.unipg.it>]
Nancy,
the first form you reported is the most stable in
water
at pH 7.0.
However, the fact that one form is more stable than
another in water
does not help you to understand which form will be
more
'relevant'
for docking. In protein the tautomeric equilibria may
produce and
stabilize different forms according to the
complementary site. There
are examples of tautomeric form in protein not stable
in water,
where the energy difference is more than 5
Kcal/mol.
MoKa software (www.moldiscovery.com
<http://www.moldiscovery.com>)
is fast and accurate to produce tautomer stable in
water, but it can
produce also all the (plausible) tautomeric
forms.
Then, a possibility is to dock them into your
protein,
to see if
docking methods may differentiate their binding.
Gabriele Cruciani
Hi All,
I am performing molecular docking and
molecular
dynamics
simulations of the
thiazolidinedione pioglitazone binding
to the
PPAR-gamma
receptor protein
(PDB ID: 1ZGY). The thiazolidinedione
ring can
exist in numerous
different
tautomeric states; I have attached a
figure
depicting several of
them.
Which tautomer would be dominant at the
physiological pH of ~7.0?
Also, are there any software programs
that can
predict which
tautomer would
be correct?
Thanks in advance,
Nancy>
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