From owner-chemistry#* at *#ccl.net Wed Jan  5 12:14:00 2011
From: "Vincent Leroux vincent.leroux#,#loria.fr" <owner-chemistry{=}server.ccl.net>
To: CCL
Subject: CCL: Thiazolidinedione Tautomers
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X-Original-From: Vincent Leroux <vincent.leroux..loria.fr>
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Date: Wed, 05 Jan 2011 18:10:40 +0100
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Sent to CCL by: Vincent Leroux [vincent.leroux_._loria.fr]
Hi Nancy,

For generating tautomers, there are various good tools available, e.g.
QUACPAC, MN.TAUTOMER.

In any case, the most stable tautomeric state at a given pH might change
upon binding - I would recommend to use multiple states explicitly for
virtual screening calculations. If you want to pick a single state (e.g.
for MD simulations), it might be better to select a low level state that
binds well rather than the most stable state in solution for the
isolated ligand, if it does not perform as well. Docking followed by
minimization (using the FF that will be used for MD) prior to MD might
greatly help in such a situation.

Vincent



Le 05/01/11 01:55, Nancy nancy5villa#gmail.com a écrit :
> Thanks for the info.  I would greatly appreciate it if anyone can
> provide as much detail as possible as to which of the tautomer(s) is
> most stable in an aqueous solution at ph 7.4.
> 
> Thanks in advance,
> Nancy
> 
> 
> On Tue, Jan 4, 2011 at 7:34 PM, Jeremy R. Greenwood
> <greenwoo^_^yeremoo.homelinux.net
> <mailto:greenwoo^_^yeremoo.homelinux.net>> wrote:
> 
>     Hi Nancy,
> 
>     > I am performing molecular docking and molecular dynamics
>     simulations of
>     > thiazolidinediones (TZDs) binding to the ligand binding domain of the
>     > PPAR-gamma receptor protein.  The thiazolidinedione ring can exist in
>     > numerous different tautomeric states; is there any particular
>     tautomer(s)
>     > that would be dominant, and thus most appropriate for docking and
>     molecular
>     > dynamics simulations, at pH 7.4?
>     >
>     > I have read the article "Metformin and glitazones: does similarity in
>     > biomolecular mechanism originate from tautomerism in these drugs?"
>     J. Phys.
>     > Org. Chem. 2008, 21 30–33, as a reference, but it does make it
>     clear as to
>     > which tautomer is most appropriate for simulating binding to a
>     receptor
>     > protein at pH 7.4.
> 
>     Since it is an acidic heterocycle, and since it is acting as
>     a bioisostere for the acid group on the endogenous ligand,
>     I recommend you simply deprotonate it (and adjust the surrounding
>     protein to match accordingly). There's only one reasonable tautomer
>     of the conjugate base anion (although you can represent it various ways,
>     with the formal -1 charge on the deprotonated nitrogen or either
>     oxygen).
> 
>     hope this helps,
> 
>     --Jeremy
> 
>