On Thu, Jan 13, 2011 at 10:31 PM, Andreas Klamt klamt(a)cosmologic.de <owner-chemistry(~)ccl.net> wrote:

Sent to CCL by: Andreas Klamt [klamt,cosmologic.de]
Hi Nancy,

as I wrote in the previous message, we find by quantum chemical calculations within the COSMO-RS solvation that the diketone form is more stable by abot 12 kcal/mol, that means it absolutely dominates!

Andreas

Am 13.01.2011 22:25, schrieb Nancy nancy5villa~!~gmail.com:

Hi All,

I happened to find a published article where molecular docking simulations of TZDs against a novel protein is detailed:

"Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET" Bioorg Med Chem Lett. 2010 Feb 1;20(3):819-23

In this paper, the authors, using MarvinSketch v3.5.4, determined that the TZDs would exist predominantly in the enol form at pH 7.4, as opposed to the diketone form (see attached figure). It appears that the article's tautomer prediction was based only on the pH prior to docking, and had nothing to do with ligand-protein interactions.

Does anyone know if the diketone or enol, or perhaps a different tautomer, would be predominant at pH 7.4?

Thanks in advance.
Nancy

On Wed, Jan 12, 2011 at 9:53 AM, Andreas Klamt klamt-*-cosmologic.de <owner-chemistry(_)ccl.net> wrote:

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>

<owner-chemistry[a]ccl.net <mailto:owner-chemistry[a]ccl.net>> wrote:

Sent to CCL by: Gabriele Cruciani [gabri##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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