CCL: Pioglitazone Tautomers

 Sent to CCL by: Vincent Leroux [vincent.leroux^loria.fr]
 Hi Nancy,
 I suppose you did docking and MD with explicit hydrogens - should be the
 case. So you did several calculations, one for each tautomeric state.
 Inspect the docking and MD results. The charge model is approximate, but
 is there any significant difference in the scores (docking) /
 protein-ligand and ligand-solvent interaction energies (MD) due to the
 tautomeric state already? Inspect the structures, especially if there
 are such differences: is the formation of a stable protein-ligand H-bond
 depending of the changing protonation state of a given atom? If so, you
 would favor the corresponding state(s).
 Secondarily, is your "variable" ligand group bound in a highly polar
 pocket? If so you might want to compute optimized charges then perform
 some MM/PBSA minimization from docking results to get a better idea of
 what could happen.
 Only after such investigations should you decide which of the remaining
 ligand state is the most relevant at pH 7, using tools specialized to do
 such predictions. Do not be tempted to select one state without looking
 at docking/MD results first. If your only parameter for selecting a
 state is the pH, you assume that going from bulk solvent to the binding
 site environment will have no influence...
 Do not forget the histidines, if there are some on the binding site...
 choosing their protonation state is a similar story. Look after H-bonds
 forming upon ligand binding, and if the picture is the same regardless
 the protonation state, then you can simply thrust the H++ server for
 example.
 Regards
 VL
 Le 10/01/11 00:09, Nancy nancy5villa]^[gmail.com a écrit :
 > 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
 >
 >