Thread: [Rdkit-discuss] Isomeric smiles and explicit hydrogens
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From: Noel O'B. <bao...@gm...> - 2008-04-14 10:50:25
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I've been trying to get my head around what's happening when I read
and write isomeric smiles. As a user, I hope that the same molecule
will also have the same isomeric SMILES. However, look at the
following examples using cinfony which read a SMILES string and write
an isomeric SMILES string...
I'm trying to specify the chirality of the carbon in
chlorobromomethane, but RDKit is not picking up on the chirality:
>>> rdk.readstring("smi", "[C](Cl)Br").write("iso")
'ClCBr'
(No chirality, as expected)
>>> rdk.readstring("smi", "[C@@H](Cl)Br").write("iso")
'Cl[CH]Br'
>>> rdk.readstring("smi", "[C@](Cl)Br").write("iso")
'ClCBr'
>>> rdk.readstring("smi", "Cl[C@]Br").write("iso")
'ClCBr'
>>> rdk.readstring("smi", "Cl[C@@H]Br").write("iso")
'Cl[CH]Br'
(Expected chirality, but didn't get it)
Let's try 1-chloro,1-bromoethane:
>>> rdk.readstring("smi", "Cl[C@@](Br)C").write("iso")
'CC(Cl)Br'
(Expected chirality, but didn't get it)
>>> rdk.readstring("smi", "Cl[C@@H](Br)C").write("iso")
'C[C@@H](Cl)Br'
(Expected chirality, and got it)
Is the problem with me or with RDKit?
On a related note, I have found that RDKit, when reading SDF files,
turns all of the hydrogens into implicit hydrogens. However, when
reading SMILES strings, it retains any explicit hydrogens specified in
C@@H expressions. This doesn't seem to be consistent and requires the
user to remove hydrogens if he/she wants to create a canonical smiles
string.
Apologies in advance if my understanding of SMILES is shaky.
Regards,
Noel
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From: Noel O'B. <bao...@gm...> - 2008-04-14 14:48:02
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I think I've been misunderstanding the square brackets. I need to
RTFM, I think, after which I'll post here again if still confused.
Noel
On 14/04/2008, Noel O'Boyle <bao...@gm...> wrote:
> I've been trying to get my head around what's happening when I read
> and write isomeric smiles. As a user, I hope that the same molecule
> will also have the same isomeric SMILES. However, look at the
> following examples using cinfony which read a SMILES string and write
> an isomeric SMILES string...
>
> I'm trying to specify the chirality of the carbon in
> chlorobromomethane, but RDKit is not picking up on the chirality:
>
> >>> rdk.readstring("smi", "[C](Cl)Br").write("iso")
> 'ClCBr'
> (No chirality, as expected)
>
> >>> rdk.readstring("smi", "[C@@H](Cl)Br").write("iso")
> 'Cl[CH]Br'
> >>> rdk.readstring("smi", "[C@](Cl)Br").write("iso")
> 'ClCBr'
> >>> rdk.readstring("smi", "Cl[C@]Br").write("iso")
> 'ClCBr'
> >>> rdk.readstring("smi", "Cl[C@@H]Br").write("iso")
> 'Cl[CH]Br'
> (Expected chirality, but didn't get it)
>
> Let's try 1-chloro,1-bromoethane:
>
> >>> rdk.readstring("smi", "Cl[C@@](Br)C").write("iso")
> 'CC(Cl)Br'
> (Expected chirality, but didn't get it)
> >>> rdk.readstring("smi", "Cl[C@@H](Br)C").write("iso")
> 'C[C@@H](Cl)Br'
> (Expected chirality, and got it)
>
> Is the problem with me or with RDKit?
>
> On a related note, I have found that RDKit, when reading SDF files,
> turns all of the hydrogens into implicit hydrogens. However, when
> reading SMILES strings, it retains any explicit hydrogens specified in
> C@@H expressions. This doesn't seem to be consistent and requires the
> user to remove hydrogens if he/she wants to create a canonical smiles
> string.
>
> Apologies in advance if my understanding of SMILES is shaky.
>
> Regards,
>
> Noel
>
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From: Noel O'B. <bao...@gm...> - 2008-04-14 14:51:49
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And (egg on face) chlorobromomethane isn't chiral in the first
place...what was I thinking?
On 14/04/2008, Noel O'Boyle <bao...@gm...> wrote:
> I've been trying to get my head around what's happening when I read
> and write isomeric smiles. As a user, I hope that the same molecule
> will also have the same isomeric SMILES. However, look at the
> following examples using cinfony which read a SMILES string and write
> an isomeric SMILES string...
>
> I'm trying to specify the chirality of the carbon in
> chlorobromomethane, but RDKit is not picking up on the chirality:
>
> >>> rdk.readstring("smi", "[C](Cl)Br").write("iso")
> 'ClCBr'
> (No chirality, as expected)
>
> >>> rdk.readstring("smi", "[C@@H](Cl)Br").write("iso")
> 'Cl[CH]Br'
> >>> rdk.readstring("smi", "[C@](Cl)Br").write("iso")
> 'ClCBr'
> >>> rdk.readstring("smi", "Cl[C@]Br").write("iso")
> 'ClCBr'
> >>> rdk.readstring("smi", "Cl[C@@H]Br").write("iso")
> 'Cl[CH]Br'
> (Expected chirality, but didn't get it)
>
> Let's try 1-chloro,1-bromoethane:
>
> >>> rdk.readstring("smi", "Cl[C@@](Br)C").write("iso")
> 'CC(Cl)Br'
> (Expected chirality, but didn't get it)
> >>> rdk.readstring("smi", "Cl[C@@H](Br)C").write("iso")
> 'C[C@@H](Cl)Br'
> (Expected chirality, and got it)
>
> Is the problem with me or with RDKit?
>
> On a related note, I have found that RDKit, when reading SDF files,
> turns all of the hydrogens into implicit hydrogens. However, when
> reading SMILES strings, it retains any explicit hydrogens specified in
> C@@H expressions. This doesn't seem to be consistent and requires the
> user to remove hydrogens if he/she wants to create a canonical smiles
> string.
>
> Apologies in advance if my understanding of SMILES is shaky.
>
> Regards,
>
> Noel
>
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From: Greg L. <gre...@gm...> - 2008-04-14 16:25:46
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Hi Noel,
You already figured out the problem with the chirality of
chlorobromomethane, but I want to clarify a couple of things below.
On Mon, Apr 14, 2008 at 12:50 PM, Noel O'Boyle <bao...@gm...> wrote:
>
> I'm trying to specify the chirality of the carbon in
> chlorobromomethane, but RDKit is not picking up on the chirality:
>
> >>> rdk.readstring("smi", "[C](Cl)Br").write("iso")
> 'ClCBr'
> (No chirality, as expected)
Just to be clear on this one, the output here is not technically
correct; you've input a molecule with the formula CClBr (you told the
software that the C has no implicit Hs by putting it in square
brackets), the output however is for something with the formula
CH2ClBr. This is actually a bug; thanks for finding it. :-)
https://sourceforge.net/tracker/index.php?func=detail&aid=1942220&group_id=160139&atid=814650
> >>> rdk.readstring("smi", "[C@@H](Cl)Br").write("iso")
> 'Cl[CH]Br'
> >>> rdk.readstring("smi", "[C@](Cl)Br").write("iso")
> 'ClCBr'
> >>> rdk.readstring("smi", "Cl[C@]Br").write("iso")
> 'ClCBr'
> >>> rdk.readstring("smi", "Cl[C@@H]Br").write("iso")
> 'Cl[CH]Br'
> (Expected chirality, but didn't get it)
As you've realized: this molecule isn't chiral, so the RDKit is doing
the right thing by not marking chirality. It's doing something
arguable with the canonical smiles though, because it's showing the
explicit H (inside the square brackets). If you input exactly the same
molecule as ClCBr, you'd get a different canonical smiles. This is a
known oddity of the way things are currently handled internally and I
haven't quite figured out a solution yet. Basically explicit Hs remain
always explicit, even if they don't need to be.
> Let's try 1-chloro,1-bromoethane:
>
> >>> rdk.readstring("smi", "Cl[C@@](Br)C").write("iso")
> 'CC(Cl)Br'
> (Expected chirality, but didn't get it)
Again, the molecule as provided isn't chiral because carbon 1 only has
three neighbors (you've told it that there are no implicit Hs).
> >>> rdk.readstring("smi", "Cl[C@@H](Br)C").write("iso")
> 'C[C@@H](Cl)Br'
> (Expected chirality, and got it)
It's even the right chirality, which is good to see. :-)
> Is the problem with me or with RDKit?
I'll answer that "or" question with a "yes", because it's a little of both. :-)
> On a related note, I have found that RDKit, when reading SDF files,
> turns all of the hydrogens into implicit hydrogens.
correct.
> However, when
> reading SMILES strings, it retains any explicit hydrogens specified in
> C@@H expressions. This doesn't seem to be consistent and requires the
> user to remove hydrogens if he/she wants to create a canonical smiles
> string.
I commented on this above. It's a known problem and I've been stewing
over how to solve it for a while. Now that someone other than me is
complaining I'll bump it up a bit in priority.
-greg
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From: Noel O'B. <bao...@gm...> - 2008-04-14 19:12:57
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If I found a bug earlier, it was completely by accident. The following
though I think is also a bug. I find that I can invert the
stereocenter by adding and removing Hs.
>>> mol = rdk.readstring("smi", "C[C@@H](O)(Cl)c1ccccc1")
>>> mol.write("iso")
'C[C@@H](O)(Cl)c1ccccc1'
>>> mol.addh()
>>> mol.write("iso")
'[H]O[C@](Cl)(C([H])([H])[H])([H])c1c([H])c([H])c([H])c([H])c1[H]'
>>> mol.removeh()
>>> mol.write("iso")
'C[C@H](O)(Cl)c1ccccc1'
Can you tell whether the problem is when I add the Hs, or when I
remove them? I might be able to workaround if the adding is working
okay.
Noel
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From: Greg L. <gre...@gm...> - 2008-04-14 20:04:05
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On Mon, Apr 14, 2008 at 9:12 PM, Noel O'Boyle <bao...@gm...> wrote:
> If I found a bug earlier, it was completely by accident. The following
> though I think is also a bug. I find that I can invert the
> stereocenter by adding and removing Hs.
>
> >>> mol = rdk.readstring("smi", "C[C@@H](O)(Cl)c1ccccc1")
> >>> mol.write("iso")
> 'C[C@@H](O)(Cl)c1ccccc1'
> >>> mol.addh()
> >>> mol.write("iso")
> '[H]O[C@](Cl)(C([H])([H])[H])([H])c1c([H])c([H])c([H])c([H])c1[H]'
> >>> mol.removeh()
> >>> mol.write("iso")
> 'C[C@H](O)(Cl)c1ccccc1'
>
> Can you tell whether the problem is when I add the Hs, or when I
> remove them? I might be able to workaround if the adding is working
> okay.
As discussed in your later message, this molecule has a 5-coordinate
C, so it probably shouldn't have the @ in the output SMILES at all.
(Sarcasm doesn't work in email: that "probably" is a joke, it
definitely shouldn't be in there; that's another nice bug).
I'm prepared to believe that there could be a bug that causes
inversion of chirality when Hs are added and removed (I wouldn't be
overly surprised), but it definitely doesn't always happen, as this
case demonstrates:
[18]>>> m = Chem.MolFromSmiles('O[C@H](F)Cl')
[19]>>> Chem.MolToSmiles(m,1)
Out[19] 'O[C@H](F)Cl'
[20]>>> m2=Chem.AddHs(m)
[21]>>> Chem.MolToSmiles(m2)
Out[21] '[H]OC(F)(Cl)[H]'
[22]>>> Chem.MolToSmiles(m2,True)
Out[22] '[H]O[C@](F)(Cl)[H]'
[23]>>> m3 = Chem.RemoveHs(m2)
[24]>>> Chem.MolToSmiles(m3,True)
Out[24] 'O[C@H](F)Cl'
After playing around a bit with a model, I think this is also ok:
[25]>>> m = Chem.MolFromSmiles('C[C@@H](O)Cl')
[27]>>> Chem.MolToSmiles(m,True)
Out[27] 'C[C@@H](O)Cl'
[28]>>> m2 = Chem.AddHs(m)
[30]>>> Chem.MolToSmiles(m2,True)
Out[30] '[H]O[C@@](Cl)(C([H])([H])[H])[H]'
[31]>>> m3 = Chem.RemoveHs(m2)
[32]>>> Chem.MolToSmiles(m3,True)
Out[32] 'C[C@@H](O)Cl'
-greg
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From: Noel O'B. <bao...@gm...> - 2008-04-14 19:33:26
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Wait a second, that molecule has five substituents on the isomeric C.
But I think we share the blame again this time, Greg, because I took
that structure from the RDKit Python tutorial Section 2.3. :-)
Noel
On 14/04/2008, Noel O'Boyle <bao...@gm...> wrote:
> If I found a bug earlier, it was completely by accident. The following
> though I think is also a bug. I find that I can invert the
> stereocenter by adding and removing Hs.
>
> >>> mol = rdk.readstring("smi", "C[C@@H](O)(Cl)c1ccccc1")
> >>> mol.write("iso")
> 'C[C@@H](O)(Cl)c1ccccc1'
> >>> mol.addh()
> >>> mol.write("iso")
> '[H]O[C@](Cl)(C([H])([H])[H])([H])c1c([H])c([H])c([H])c([H])c1[H]'
> >>> mol.removeh()
> >>> mol.write("iso")
> 'C[C@H](O)(Cl)c1ccccc1'
>
> Can you tell whether the problem is when I add the Hs, or when I
> remove them? I might be able to workaround if the adding is working
> okay.
>
>
> Noel
>
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From: Greg L. <gre...@gm...> - 2008-04-14 19:54:30
|
On Mon, Apr 14, 2008 at 9:33 PM, Noel O'Boyle <bao...@gm...> wrote: > Wait a second, that molecule has five substituents on the isomeric C. > But I think we share the blame again this time, Greg, because I took > that structure from the RDKit Python tutorial Section 2.3. :-) Indeed. That's a documentation bug. I'll fix it. There's also something bad in general going on with the handling of organic-subset atoms in square brackets that I'm going to have to track down (I think the five coordinate neutral C should have caused an error). Thanks for reporting it. -greg |
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