[gmx-users] Thiazolidinedione Tautomers

[Mark Abraham]

On 3/01/2011 11:15 AM, Nancy wrote:
> Hi All,
>
> 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 (see attached figure); is 
> there any particular tautomer(s) that would be dominant, and thus most 
> appropriate for docking and molecular dynamics simulations, at pH 7.4?

This sounds like the kind of question that is best answered by docking - 
and preferably only when the receptor site is not very flexible and 
lacks many titratable sites and lacks potential for water bridging. Any 
educated guesswork based on general chemical principles (or EM using MM 
or QM) will be doubtfully valid because of the specific steric and 
polarization contexts of the receptor site. I dunno if there are any 
sexy NMR techniques that can prune the list of candidates.

Mark

> 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.
>
> Thanks in advance,
> Nancy
>