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problems/inconsistancies in major microspecies prediction
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Lowell

Joined: 20 Nov 2007
Posts: 14

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Link to postPosted: Thu Aug 06, 2015 12:29 amPost subject: problems/inconsistancies in major microspecies prediction Reply with quote

Hello,

I have some structures where I used Marvin to generate the major microspecies at pH 2.5.

There are several compounds where the predicted major microspecies is inconsistent with the predicted pKa. There are nitrogen atoms with predicted pKa values ranging from 3.92 to 7.32 and the major microspecies still shows no protonated centers. As far as I can tell from looking at other compounds, if the microspecies is specified at pH 2.5, a center with the a predicted pKa of 2.5 or greater will show as protonated. This is for the first pka as none of these compounds show any protonated centers. Certainly if the first pKa for a compound is over 3.5 it should show as protonated at pH 2.5.

Here is a list of problem compounds, the pKa is given first

2.65 C[NH+]1C(C)=CC(=O)C=C1C
5.49 CC1(C)CC2=CC=CC=C2C(N1)=C1C(=O)CCCC1=O
3.92 CN(C)NC1=CC(=O)CC(C1)C1=CC=CC=C1
7.32 CCCCNC=C1C(=O)CC(CC1=O)C1=CC=CC=C1
5.31 O=C1CCCC(NC2=CC=CC=C2)=C1
4.41 CC1(C)CC(=O)C=C(C1)NC1=C(NC2=CC(=O)CC(C)(C)C2)C=CC=C1
4.31 O=C1CCCC(=O)C1=CNC1=CC=CC2=CC=CC=C12
5.05 CCCCC1=CC=C(NC=CC(=O)C2=CC=C(C)C=C2)C=C1

The first compound has a predicted pKa of 2.65 and shows as protonated. The rest all have higher predicted pKa values and don't show as protonated. Each of these compounds has at least one alpha beta unsaturated ketone group in a conjugated system with an amine. One can question the predicted pKa since many of these nitrogen atoms will exhibit amide like characteristics because of the conjugated connection to the strongly  withdrawing ketone, but at the least the major microspecies predictions should be consistent with the pKa prediction.

Any suggestions here?

LH

 

Jozsef
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Joined: 25 May 2004
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Link to postPosted: Thu Aug 06, 2015 10:04 amPost subject: Reply with quote

Hi,

 

Yes, you are right. Something is very confused in  the presented results both in the pKa and the major forms. Amine pKa should be more lower in this compounds. And the major forms should be coincident with the pKa values. 

I tried a recently released Marvin version and it is OK. I propose you to update your version. 

Your questions will be answered my colleagues.

Jozsi

Lowell

Joined: 20 Nov 2007
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Link to postPosted: Thu Aug 06, 2015 10:40 pmPost subject: Reply with quote

Jozsi wrote:

Hi,

 

Yes, you are right. Something is very confused in  the presented results both in the pKa and the major forms. Amine pKa should be more lower in this compounds. And the major forms should be coincident with the pKa values. 

I tried a recently released Marvin version and it is OK. I propose you to update your version. 

Your questions will be answered my colleagues.

Jozsi

I will re-run with the most recent version and see if I get different results. There are a few other odd issues, but I will wait on those until I see if they are persistent in the latest version.

At first glance, there are 171 compounds whose SMILES is different with the new version compared to the older version. I will have to go through the specific compounds and see what has changed.

LH

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