On 3/01/2011 12:54 PM, Nancy wrote:
Hi All,
In the figure illustrating the various tautomers, some are actually
aromatic; wouldn't these be the predominant species at pH 7.4?
I see the diol conformers would be aromatic, however do note that
thiophene is less aromatic than furan, so perhaps the aromaticity is not
a strong effect here.
Also, how could one start docking without a properly defined ligand?
As you would for any ligand for which ligand conformation would not be
an issue - by supplying some kind of coordinate file. Here, however, you
will need to try several conformations systematically. Note that this is
fairly off-topic for this list, so please consult the resources of your
docking program for details.
Mark
Thanks in advance,
Nancy
On Sun, Jan 2, 2011 at 8:30 PM, Mark Abraham <[email protected]
<mailto:[email protected]>> wrote:
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
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