Chirality and tetrahedral stereo configuration

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Chirality and tetrahedral stereo configuration

Stefano Forli
Hi all,

I'm trying to enumerate all enantiomers for chiral centers in a given molecule, and I'm
using the following Python code:

   org = self.facade.GetTetrahedralStereo(idx).GetConfig().refs
   new = ( org[1], org[0], org[2] )
   self.chiralSet.append((org, new))

This code works well most of the times. Problems arise with molecules like
"CC1CCCC[NH+]1C", in which nitrogen has as a tetrahedral configuration defined, but the
carbon (C1) doesn't.

Is there a better way to deal with chirality and avoid this issue?

Thanks,

S


--

  Stefano Forli, PhD

  Assistant Professor of Integrative
  Structural and Computational Biology,
  Molecular Graphics Laboratory

  Dept. of Integrative Structural
   and Computational Biology, MB-112A
  The Scripps Research Institute
  10550  North Torrey Pines Road
  La Jolla,  CA 92037-1000,  USA.

     tel: +1 (858)784-2055
     fax: +1 (858)784-2860
     email: [hidden email]
     http://www.scripps.edu/~forli/

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Re: Chirality and tetrahedral stereo configuration

Noel O'Boyle
Administrator
There are some bugs in the stereo perception, and this looks like one.
Was the molecule read in from SMILES?

 It might be worth compiling a list of all problematic molecules you
come across (well, one example of each type) so that a future
developer can fix this.

Regards,
- Noel

On 27 April 2016 at 01:29, Stefano Forli <[hidden email]> wrote:

> Hi all,
>
> I'm trying to enumerate all enantiomers for chiral centers in a given molecule, and I'm
> using the following Python code:
>
>    org = self.facade.GetTetrahedralStereo(idx).GetConfig().refs
>    new = ( org[1], org[0], org[2] )
>    self.chiralSet.append((org, new))
>
> This code works well most of the times. Problems arise with molecules like
> "CC1CCCC[NH+]1C", in which nitrogen has as a tetrahedral configuration defined, but the
> carbon (C1) doesn't.
>
> Is there a better way to deal with chirality and avoid this issue?
>
> Thanks,
>
> S
>
>
> --
>
>   Stefano Forli, PhD
>
>   Assistant Professor of Integrative
>   Structural and Computational Biology,
>   Molecular Graphics Laboratory
>
>   Dept. of Integrative Structural
>    and Computational Biology, MB-112A
>   The Scripps Research Institute
>   10550  North Torrey Pines Road
>   La Jolla,  CA 92037-1000,  USA.
>
>      tel: +1 (858)784-2055
>      fax: +1 (858)784-2860
>      email: [hidden email]
>      http://www.scripps.edu/~forli/
>
> ------------------------------------------------------------------------------
> Find and fix application performance issues faster with Applications Manager
> Applications Manager provides deep performance insights into multiple tiers of
> your business applications. It resolves application problems quickly and
> reduces your MTTR. Get your free trial!
> https://ad.doubleclick.net/ddm/clk/302982198;130105516;z
> _______________________________________________
> OpenBabel-discuss mailing list
> [hidden email]
> https://lists.sourceforge.net/lists/listinfo/openbabel-discuss

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Re: Chirality and tetrahedral stereo configuration

Stefano Forli
Noel,
thanks for the reply.
I thought it was a mistake in my code, so I collected a few of those problematic molecules
because I have to deal with them very often (once I didn't notice them and they sneaked
into some results, making the synthetic chemists fairly nervous).

When debugging it, I found that the problem seems to be independent from the input format,
and I've tried all combinations of data (i.e., 1D, 2D and 3D):

 >> CC1CCCC[NH+]1C [format: smi]
chiral: 2 [ elem: 6]
   - has no TS config
   - refs: (1L, 7L, 3L)
   - chirality fixed:  False
chiral: 7 [ elem: 7]
   - has no TS config
   - refs: (6L, 8L, 2L)
   - chirality fixed:  False

 >> C[C@H]1CCCC[N@@H+]1C [format: smi, 1D]
chiral: 2 [ elem: 6]
- has no TS config
- refs: (1L, 3L, 8L)
- chirality fixed: False
chiral: 8 [ elem: 7]
- has no TS config
- refs: (7L, 9L, 2L)
- chirality fixed: False

 >> [NH+]1(C(CCCC1)C)C [format: mol2, 2D]
chiral: 1 [ elem: 7]
- has TS config
- refs: (2L, 6L, 4294967294L)
chiral: 2 [ elem: 6]
- has no TS config
- refs: (1L, 3L, 7L)
- chirality fixed: False

 >> [N@H+]1([C@H](CCCC1)C)C [format: mol2, 3D]
chiral: 1 [ elem: 7]
- has TS config
- refs: (2L, 9L, 6L)
chiral: 2 [ elem: 6]
- has no TS config
- refs: (1L, 3L, 7L)
- chirality fixed: False

I remember Geoff fixed some of the problems related to chirality in in rings (with the
distance geometry approach, I believe). Unfortunately, even with the latest code from GIT
the problem I reported still persists.
Let me know what I can do to help fixing the issue.

Thanks,

S


On 04/27/2016 01:42 AM, Noel O'Boyle wrote:

> There are some bugs in the stereo perception, and this looks like one.
> Was the molecule read in from SMILES?
>
>   It might be worth compiling a list of all problematic molecules you
> come across (well, one example of each type) so that a future
> developer can fix this.
>
> Regards,
> - Noel
>
> On 27 April 2016 at 01:29, Stefano Forli <[hidden email]> wrote:
>> Hi all,
>>
>> I'm trying to enumerate all enantiomers for chiral centers in a given molecule, and I'm
>> using the following Python code:
>>
>>     org = self.facade.GetTetrahedralStereo(idx).GetConfig().refs
>>     new = ( org[1], org[0], org[2] )
>>     self.chiralSet.append((org, new))
>>
>> This code works well most of the times. Problems arise with molecules like
>> "CC1CCCC[NH+]1C", in which nitrogen has as a tetrahedral configuration defined, but the
>> carbon (C1) doesn't.
>>
>> Is there a better way to deal with chirality and avoid this issue?
>>
>> Thanks,
>>
>> S
>>
>>
>> --
>>
>>    Stefano Forli, PhD
>>
>>    Assistant Professor of Integrative
>>    Structural and Computational Biology,
>>    Molecular Graphics Laboratory
>>
>>    Dept. of Integrative Structural
>>     and Computational Biology, MB-112A
>>    The Scripps Research Institute
>>    10550  North Torrey Pines Road
>>    La Jolla,  CA 92037-1000,  USA.
>>
>>       tel: +1 (858)784-2055
>>       fax: +1 (858)784-2860
>>       email: [hidden email]
>>       http://www.scripps.edu/~forli/
>>
>> ------------------------------------------------------------------------------
>> Find and fix application performance issues faster with Applications Manager
>> Applications Manager provides deep performance insights into multiple tiers of
>> your business applications. It resolves application problems quickly and
>> reduces your MTTR. Get your free trial!
>> https://ad.doubleclick.net/ddm/clk/302982198;130105516;z
>> _______________________________________________
>> OpenBabel-discuss mailing list
>> [hidden email]
>> https://lists.sourceforge.net/lists/listinfo/openbabel-discuss

--

  Stefano Forli, PhD

  Assistant Professor of Integrative
  Structural and Computational Biology,
  Molecular Graphics Laboratory

  Dept. of Integrative Structural
   and Computational Biology, MB-112A
  The Scripps Research Institute
  10550  North Torrey Pines Road
  La Jolla,  CA 92037-1000,  USA.

     tel: +1 (858)784-2055
     fax: +1 (858)784-2860
     email: [hidden email]
     http://www.scripps.edu/~forli/

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Re: Chirality and tetrahedral stereo configuration

Geoff Hutchison
> I remember Geoff fixed some of the problems related to chirality in in rings (with the
> distance geometry approach, I believe). Unfortunately, even with the latest code from GIT

No, there is a maddening bug with chiral constraints with the distance geometry builder. In principal, DG can ensure the resulting geometry matches all stereochemical constraints (e.g., RDKit, smi23d, etc.) I have not had the time to figure out why the correction procedure fails to fix stereochemistry on complex molecules.

I had assumed the stereo code was solid. I'm happy to take a look at a few of these bugs, but they may have to wait until 2.4.1 - I think it's far past time to make a release.

-Geoff


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