From owner-chemistry@ccl.net Fri Jan 14 01:32:01 2011 From: "Andreas Klamt klamt(a)cosmologic.de" To: CCL Subject: CCL: Pioglitazone Tautomers Message-Id: <-43634-110113223127-19204-JPYcouHcfoDsO0iPV6jDKg~!~server.ccl.net> X-Original-From: Andreas Klamt Content-Transfer-Encoding: 7bit Content-Type: text/html; charset=ISO-8859-1 Date: Fri, 14 Jan 2011 04:31:14 +0100 MIME-Version: 1.0 Sent to CCL by: Andreas Klamt [klamt,cosmologic.de] Hi Nancy,

as I wrote in the previous message, we find by quantum chemical calculations within the COSMO-RS solvation that the diketone form is more stable by abot 12 kcal/mol, that means it absolutely dominates!

Andreas

Am 13.01.2011 22:25, schrieb Nancy nancy5villa~!~gmail.com:
Hi All,

I happened to find a published article where molecular docking simulations of TZDs against a novel protein is detailed:

"Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET" Bioorg Med Chem Lett. 2010 Feb 1;20(3):819-23

In this paper, the authors, using MarvinSketch v3.5.4, determined that the TZDs would exist predominantly in the enol form at pH 7.4, as opposed to the diketone form (see attached figure).  It appears that the article's tautomer prediction was based only on the pH prior to docking, and had nothing to do with ligand-protein interactions.

Does anyone know if the diketone or enol, or perhaps a different tautomer, would be predominant at pH 7.4?

Thanks in advance.
Nancy



On Wed, Jan 12, 2011 at 9:53 AM, Andreas Klamt klamt-*-cosmologic.de <owner-chemistry(_)ccl.net> wrote:

Sent to CCL by: Andreas Klamt [klamt[*]cosmologic.de]
Hi All,

let me put my 5 cents into the game:
We have done quantum calculations for the heterocyclic ring, with just a methyl group, since electronically the remainder of the compound should have almost no influence on the heterocycle.
DFT/COSMO-RS calculations prove the neutral species
SMILES:CC1C(=O)[NH]C(=O)S1 of the Pioglitazone heterocycle to be favored by 11.3 kcal/mol compared to all other neutral species of the heterocycle, which means that there is no other relvant neutral form.

We find with COSMOtherm that the pka of the heterocycle is 6.55, i.e. at pH=7 it should be deprotonated with about 25%.
Since the pka of the conj. acid of the pyridine ring according to COSMOtherm (we calculated diethylpyridine) is ~5.6 there should be ~10% in the zwitterionic form.

It will be hard to decide this finally, unless someone measures it, but we are quite confident to be qualitatively right here, because the energy differences for the tautomers should not have more than 5 kcal/mol erro, as we learned in in the SAMPL2 tautomer contest:
see Andreas Klamt and Michael Diedenhofen, Some conclusions regarding the predictions of tautomeric equilibria in solution based on the SAMPL2 challenge, http://www.springerlink.com/content/l577667th758n6h1/

Andreas







Hi All,

Using MarvinSketch v5.3.3 (ChemAxon software), the predicted pKa value
of the acidic hydrogen on the thiazolidinedione ring of pioglitazone is
4.57 (see attached "Figure_1.gif"). Therefore, the predominant species
at pH 7.0 predicted by MarvinSketch is the one depicted in
"Figure_2.gif". The different tautomeric forms predicted by MarvinSketch
are shown in "Figure_3.gif".

Can anyone explain where these predictions come from, and if they are
correct?

Thanks,
Nancy


On Mon, Jan 10, 2011 at 4:16 AM, Gabriele Cruciani
gabri(0)chemiome.chm.unipg.it <http://chemiome.chm.unipg.it>

<owner-chemistry[a]ccl.net <mailto:owner-chemistry[a]ccl.net>> wrote:


   Sent to CCL by: Gabriele Cruciani [gabri##chemiome.chm.unipg.it
   <http://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 <http://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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From owner-chemistry@ccl.net Fri Jan 14 05:59:00 2011 From: "neeraj misra neerajmisra\a/hotmail.com" To: CCL Subject: CCL: MSP CALCULATION Message-Id: <-43635-110114055553-30393-MIEw7ym/++UUcCjG3mnKpQ||server.ccl.net> X-Original-From: "neeraj misra" Date: Fri, 14 Jan 2011 05:55:52 -0500 Sent to CCL by: "neeraj misra" [neerajmisra===hotmail.com] ANY SUGGESTIONS FOR HOW TO CALCULATE 2 DIMENSIONAL ESP BY GAUSSVIEW.. From owner-chemistry@ccl.net Fri Jan 14 16:06:00 2011 From: "Seth Olsen s.olsen1#,#uq.edu.au" To: CCL Subject: CCL:G: Wavefunction stability Message-Id: <-43636-110113175409-31134-kSKO6enKpedwKe585aHRQA+/-server.ccl.net> X-Original-From: Seth Olsen Content-Transfer-Encoding: 8bit Content-Type: text/plain; charset="us-ascii" Date: Fri, 14 Jan 2011 08:53:57 +1000 MIME-Version: 1.0 (iPad Mail 8C148) Sent to CCL by: Seth Olsen [s.olsen1[#]uq.edu.au] The question of what orbitals are "right" for CASSCF is generally ill-posed if asked unconditionally, particularly for state-averaged problems. However, to proceed in a reasonable fashion, I recommend that you be guided at first by the occupations of the UHF natural charge (I.e. Spin-averaged) orbitals. This is easily done with molpro; look up the "natural" option to UHF. Also lookup the UNO-CAS references it cites. This should be a good way to approach the problem. -Seth Sent from my iPad On 14/01/2011, at 4:47, "Peeter Burk peeter.burk**ut.ee" wrote: > > Sent to CCL by: "Peeter Burk" [peeter.burk__ut.ee] > Dear Gerald, > > Thank you for suggestions, but I still have some doubts. Namely, I also > suspected that the system might need multiconfigurational approach and > made some CCSD(T) calculations to get the T1 diagnostic. It was quite OK > (>0.01), indicating that system can be described by single determinant > based methods. Or am I wrong here? > > Another question I have is regarding possibility of CAS type methods. As > much as I understand (and that understanding is definitely very limited) > one has to choose carefully the orbitals included in active space. Now, if > I would like to study the bigger piece of PES, how can one assure that the > "right" orbitals are chosen? Is it enough to have the same size of active > space to compare the energies of different species? > > Best regards > Peeter > >> >> Sent to CCL by: Gerald Knizia [knizia-,-theochem.uni-stuttgart.de] >> On Wednesday 12 January 2011 17:49, Peeter Burk peeter#%#chem.ut.ee wrote: >>> I seem to have both conceptually and technically troubles with >>> wavefunction >>> (wf) stabilities. >>> >>> The first solution for my system (singlet) had RHF->UHF instability. So >>> I >>> turned to UHF calculations, which had the internal instability. By using >>> Stable=Opt (using Gaussian09) I was finally able to get stable UHF wf. >>> However, the geometry optimization resulted a solution, where the wf had >>> again a internal instability, [...] >>> >>> So what does this all tell about the studied system? >> >> It tells you that this is a strong multi-reference system and that you >> should >> not attempt to describe it with Hartree-Fock or DFT. >> >>> Should it be studied by some multiconfigurational approach (I'm >>> intending >>> to study a bigger part of PES with many minima and TS-s)? >> >> Yes. >> >>> Can the coupled clusters theory be the solution? >> >> CCSD(T) can handle some degree of multiconfigurational character of >> systems. >> But it's rather limited in that regard. If you are not able to obtain a >> definite ground state Hartree-Fock solution, CCSD(T) cannot be trusted >> either. >> >>> But then again it will definitely be slower, especially as there are no >>> analytical force constants (at least in Gaussian). >> >> There are some other problems having analytical gradients for CASSCF/MCSCF >> and >> CASPT2/RS2. >> -- >> Gerald Knizia> > From owner-chemistry@ccl.net Fri Jan 14 17:47:00 2011 From: "David Sherrill sherrill|,|gatech.edu" To: CCL Subject: CCL: Georgia Tech Summer Theory Program Message-Id: <-43637-110114111958-5431-pkh4Q+TsxFUo46uGSni0Zw..server.ccl.net> X-Original-From: David Sherrill Content-Type: TEXT/PLAIN; format=flowed; charset=US-ASCII Date: Fri, 14 Jan 2011 11:19:40 -0500 (EST) MIME-Version: 1.0 Sent to CCL by: David Sherrill [sherrill~~gatech.edu] Georgia Tech will host its annual Summer Theory Program as part of its NSF-sponsored Research Experiences for Undergraduates (REU) program in chemistry and biochemistry. The ten-week program runs from May 24 to July 30 and is open to students who will be in their junior or senior years during the next academic year. Theory students will work with Professors David Sherrill, Rigoberto Hernandez, Jean-Luc Bredas, or Angelo Bongiorno in the areas of electronic structure theory, nonequilibrium dynamics, electronic properties of materials, or condensed-matter simulations. The research experience is supplemented by an introductory lecture series in theoretical chemistry. Successful applicants will receive a stipend of $4500, a travel allowance, and housing. Further details are available at http://vergil.chemistry.gatech.edu/opp/summer.html and http://www.chemistry.gatech.edu/undergraduate/summer/index.php The deadline for applications is February 15, 2011. Early submissions are encouraged. -- C. David Sherrill, Ph.D. Professor School of Chemistry & Biochemistry School of Computational Science and Engineering Georgia Institute of Technology www.chemistry.gatech.edu/faculty/Sherrill/ sherrill#%#gatech.edu, tel: 404-894-4037, fax: 404-894-7452