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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