From owner-chemistry@ccl.net Sun Jan 16 13:51:00 2011 From: "Nancy nancy5villa**gmail.com" To: CCL Subject: CCL: Pioglitazone Tautomers Message-Id: <-43658-110116132929-1728-gZpXEmPpgqrQNFY3DBy5tQ/./server.ccl.net> X-Original-From: Nancy Content-Type: multipart/alternative; boundary=00248c11da372a17cd0499fad862 Date: Sun, 16 Jan 2011 13:29:14 -0500 MIME-Version: 1.0 Sent to CCL by: Nancy [nancy5villa[]gmail.com] --00248c11da372a17cd0499fad862 Content-Type: text/plain; charset=ISO-8859-1 Content-Transfer-Encoding: quoted-printable Using quantum chemical calculations, you found that the diketone form is dominant; does this mean that the enol form predicted by MarvinSketch v3.5.= 4 in the published article is wrong? "Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET" Bioorg Med Chem Lett. 2010 Feb 1;20(3):819-23 Thanks, Nancy On Thu, Jan 13, 2011 at 10:31 PM, Andreas Klamt klamt(a)cosmologic.de < owner-chemistry,+,ccl.net> wrote: > 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 simulation= s > 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 th= e > 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 tauto= mer > 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(=3DO)[NH]C(=3DO)S1 of the Pioglitazone heterocycle to be fav= ored >> by 11.3 kcal/mol compared to all other neutral species of the heterocycl= e, >> 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=3D7 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 th= e >> 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 MarvinSketc= h >>> 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 >>> >>> > wrote: >>> >>> >>> Sent to CCL by: Gabriele Cruciani [gabri##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 ) >>> >>> 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> >>> >>> >>> E-mail to subscribers: CHEMISTRY[a]ccl.net >>> or use:> >>> E-mail to administrators: CHEMISTRY-REQUEST[a]ccl.net >>> or useConferences: >>> >>> http://server.ccl.net/chemistry/announcements/conferences/> >>> >>> >>> >>> >> -- >> Dr. Jens Reinisch >> Chemist / Customer Support >> COSMOlogic GmbH & Co. KG >> Burscheider Strasse 515 >> D-51381 Leverkusen, Germany >> >> phone +49-2171-363664 >> mobile +49-163-7337310 >> fax +49-2171-731689 >> e-mail reinisch[*]cosmologic.de >> web www.cosmologic.de >> >> HRA 20653 Amtsgericht Koeln, GF: Dr. Andreas Klamt >> Komplementaer: COSMOlogic Verwaltungs GmbH >> HRB 49501 Amtsgericht Koeln, GF: Dr. Andreas Klamt >> >> >> >> >> >> >> E-mail to subscribers: CHEMISTRY(_)ccl.net or >> use:>> >> E-mail to administrators: CHEMISTRY-REQUEST(_)ccl.netor useConferences: >> http://server.ccl.net/chemistry/announcements/conferences/>> >> >> > > > -- > PD. Dr. Andreas Klamt > CEO / Gesch=E4ftsf=FChrer > COSMOlogic GmbH & Co. KG > Burscheider Strasse 515 > D-51381 Leverkusen, Germany > > phone +49-2171-731681 > fax +49-2171-731689 > e-mail klamt(_)cosmologic.de > > web www.cosmologic.de > > HRA 20653 Amtsgericht Koeln, GF: Dr. Andreas Klamt > Komplementaer: COSMOlogic Verwaltungs GmbH > HRB 49501 Amtsgericht Koeln, GF: Dr. Andreas Klamt > > -=3D This is automatically added to each message by the mailing script = =3D- To > recover the email address of the author of the message, please change the > strange characters on the top line to the ,+, sign. You can also look up th= e > X-Original-From: line in the mail header. E-mail to subscribers: > CHEMISTRY,+,ccl.net or use:= E-mail to administrators: > CHEMISTRY-REQUEST,+,ccl.net or useBefore posting, check wait > time at: http://www.ccl.netConferences: > http://server.ccl.net/chemistry/announcements/conferences/ Search > Messages: http://www.ccl.net/chemistry/searchccl/index.shtml If your mail > bounces from CCL with 5.7.1 error, check:= RTFI: > http://www.ccl.net/chemistry/aboutccl/instructions/ --00248c11da372a17cd0499fad862 Content-Type: text/html; charset=ISO-8859-1 Content-Transfer-Encoding: quoted-printable Using quantum chemical calculations, you found that the diketone form is do= minant; does this mean that the enol form predicted by MarvinSketch v3.5.4 = in the published article is wrong?

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

Thanks,
Nancy


On Thu, Jan 13, = 2011 at 10:31 PM, Andreas Klamt klamt(a)co= smologic.de <owner-chemistry,+,ccl.net> wrote:
Sent to CCL by: Andreas Klamt [klamt,cosmologic.de] =20 =20 =20
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).=A0 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-*-co= smologic.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(=3DO)[NH]C(=3DO)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=3D7 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.c= om/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 pred= icted 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.n= et>> wrote:


=A0 =A0Sent to CCL by: Gabriele Cruciani [gabri##chemiome.chm.unipg.it
=A0 =A0<http://chemiome.chm.unipg.it>]

=A0 =A0Nancy,
=A0 =A0the first form you reported is the most stable in wate= r at pH 7.0.
=A0 =A0However, the fact that one form is more stable than another in water
=A0 =A0does not help you to understand which form will be mor= e 'relevant'
=A0 =A0for docking. In protein the tautomeric equilibria may produce and
=A0 =A0stabilize different forms according to the complementary site. There
=A0 =A0are examples of tautomeric form in protein not stable in water,
=A0 =A0where the energy difference is more than 5 Kcal/mol.
=A0 =A0MoKa software (www.moldiscovery.com <h= ttp://www.moldiscovery.com>)

=A0 =A0is fast and accurate to produce tautomer stable in water, but it can
=A0 =A0produce also all the (plausible) tautomeric forms.

=A0 =A0Then, a possibility is to dock them into your protein, to see if
=A0 =A0docking methods may differentiate their binding.

=A0 =A0Gabriele Cruciani




=A0 =A0 =A0 =A0Hi All,

=A0 =A0 =A0 =A0I am performing molecular docking and molecula= r dynamics
=A0 =A0 =A0 =A0simulations of the
=A0 =A0 =A0 =A0thiazolidinedione pioglitazone binding to the PPAR-gamma
=A0 =A0 =A0 =A0receptor protein
=A0 =A0 =A0 =A0(PDB ID: 1ZGY). The thiazolidinedione ring can exist in numerous
=A0 =A0 =A0 =A0different
=A0 =A0 =A0 =A0tautomeric states; I have attached a figure depicting several of
=A0 =A0 =A0 =A0them.
=A0 =A0 =A0 =A0Which tautomer would be dominant at the physiological pH of ~7.0?

=A0 =A0 =A0 =A0Also, are there any software programs that can predict which
=A0 =A0 =A0 =A0tautomer would
=A0 =A0 =A0 =A0be correct?

=A0 =A0 =A0 =A0Thanks in advance,
=A0 =A0 =A0 =A0Nancy>


=A0 =A0E-mail to subscribers: CHEMISTRY[a]ccl.net
=A0 =A0<mailto:CHEMISTRY[a]ccl.net&= gt; or use:>
=A0 =A0E-mail to administrators: CHEMISTRY-REQUEST[a]ccl.net
=A0 =A0<mailto:CHEMISTRY-REQUEST[a]ccl.net> or useConferences:

--
Dr. Jens Reinisch
Chemist / Customer Support
COSMOlogic GmbH & Co. KG
Burscheider Strasse 515
D-51381 Leverkusen, Germany

phone =A0 +49-2171-363664
mobile =A0+49-163-7337310
fax =A0 =A0 +49-2171-731689
e-mail =A0reinisch[*]cosmologic.de
web =A0 =A0 www.cosmologic.de

HRA 20653 Amtsgericht Koeln, GF: Dr. Andreas Klamt
Komplementaer: COSMOlogic Verwaltungs GmbH
HRB 49501 Amtsgericht Koeln, GF: Dr. Andreas Klamt 



--=20
PD. Dr. Andreas Klamt
CEO / Gesch=E4ftsf=FChrer
COSMOlogic GmbH & Co. KG
Burscheider Strasse 515
D-51381 Leverkusen, Germany

phone  	+49-2171-731681
fax    	+49-2171-731689
e-mail 	klam=
t(_)cosmologic.de

web    	www.cosmolog=
ic.de

HRA 20653 Amtsgericht Koeln, GF: Dr. Andreas Klamt
Komplementaer: COSMOlogic Verwaltungs GmbH
HRB 49501 Amtsgericht Koeln, GF: Dr. Andreas Klamt
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