CCL:G: Pioglitazone Tautomers

On Mon, Jan 10, 2011 at 4:16 AM, Gabriele Cruciani gabri(0)chemiome.chm.unipg.it <owner-chemistry|-|ccl.net> wrote:

Sent to CCL by: Gabriele Cruciani [gabri##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) 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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