Re: [Rdkit-discuss] Stereochemistry issue for spirocycles/pseudochiral centres(?)

[Greg Landrum]

To close the loop on this: the bug fix is now merged onto master. The ring
stereochemistry code now handles spiro centers.
Here's the little demo of that:

In [2]: print(Chem.CanonSmiles('O[C@H]1CC[C@]11CC[C@@](Cl)(Br)CC1'))
O[C@H]1CC[C@]12CC[C@@](Cl)(Br)CC2

Unlike previously (see the bug report) the stereochemistry info is no
longer being lost.

Since the stereochem info is still there it will be used in the conformer
generation/filtering.

-greg



On Wed, Feb 8, 2017 at 4:45 AM, Greg Landrum  wrote:

> Hi James,
>
> This is definitely a bug. The problem seems to be connected to the way
> what the RDKit calls "ring stereochemistry" is handled when there are spiro
> linkages.
>
> Here's the github issue: https://github.com/rdkit/rdkit/issues/1294
>
> I'll take a look.
>
> Best,
> -greg
>
>
>
> On Tue, Feb 7, 2017 at 8:32 PM, James Davidson 
> wrote:
>
>> Dear All,
>>
>>
>>
>> I have hit what I think is a problem with stereochemistry
>> perception/handling for certain types of pseudochiral and/or spirocyclic
>> systems.
>>
>> Basically I am observing that some types of input tetrahedral
>> stereochemical information gets lost when an RDKit molecule is generated.
>>
>> But I only realised this because I was wanting to generate conformers and
>> was seeing stereochemical scrambling…
>>
>>
>>
>> Anyway, an example with pictures will probably explain things better:
>>
>> https://gist.github.com/jepdavidson/fdfbf6366a17f4829de3d4de22f3b442
>>
>>
>>
>> Any help/advice appreciated.
>>
>>
>>
>> Kind regards
>>
>>
>>
>> James
>>
>> __
>> PLEASE READ: This email is confidential and may be privileged. It is
>> intended for the named addressee(s) only and access to it by anyone else is
>> unauthorised. If you are not an addressee, any disclosure or copying of the
>> contents of this email or any action taken (or not taken) in reliance on it
>> is unauthorised and may be unlawful. If you have received this email in
>> error, please notify the sender or postmas...@vernalis.com. Email is not
>> a secure method of communication and the Company cannot accept
>> responsibility for the accuracy or completeness of this message or any
>> attachment(s). Please check this email for virus infection for which the
>> Company accepts no responsibility. If verification of this email is sought
>> then please request a hard copy. Unless otherwise stated, any views or
>> opinions presented are solely those of the author and do not represent
>> those of the Company.
>>
>> The Vernalis Group of Companies
>> 100 Berkshire Place
>> Wharfedale Road
>> Winnersh, Berkshire
>> RG41 5RD, England
>> Tel: +44 (0)118 938  <+44%20118%20938%20>
>>
>> To access trading company registration and address details, please go to
>> the Vernalis website at www.vernalis.com and click on the "Company
>> address and registration details" link at the bottom of the page..
>> __
>>
>> 
>> --
>> Check out the vibrant tech community on one of the world's most
>> engaging tech sites, SlashDot.org! http://sdm.link/slashdot
>> ___
>> Rdkit-discuss mailing list
>> Rdkit-discuss@lists.sourceforge.net
>> https://lists.sourceforge.net/lists/listinfo/rdkit-discuss
>>
>>
>
--
Check out the vibrant tech community on one of the world's most
engaging tech sites, SlashDot.org! http://sdm.link/slashdot___
Rdkit-discuss mailing list
Rdkit-discuss@lists.sourceforge.net
https://lists.sourceforge.net/lists/listinfo/rdkit-discuss

Re: [Rdkit-discuss] Stereochemistry issue for spirocycles/pseudochiral centres(?)

[Greg Landrum]

To further help with the work-around: it's safe to sanitize the molecule,
but you cannot call Chem.AssignStereochemistry(), which the SMILES parser
does when you tell it to sanitize.
Here's an example from your gist:

In [2]: m3 = Chem.MolFromSmiles('O[C@H]1CC[C@]11CC[C@@](Cl)(Br)CC1',
sanitize=False)

In [3]: for atom in m3.GetAtoms():
   ...: print("Stereo:", atom.GetChiralTag(), "Neighbours:",
[n.GetSymbol() for n in atom.GetNeighbors()])
   ...:
Stereo: CHI_UNSPECIFIED Neighbours: ['C']
Stereo: CHI_TETRAHEDRAL_CW Neighbours: ['O', 'C', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']
Stereo: CHI_TETRAHEDRAL_CCW Neighbours: ['C', 'C', 'C', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']
Stereo: CHI_TETRAHEDRAL_CW Neighbours: ['C', 'Cl', 'Br', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']

In [4]: Chem.SanitizeMol(m3)
Out[4]: rdkit.Chem.rdmolops.SanitizeFlags.SANITIZE_NONE

In [5]: for atom in m3.GetAtoms():
   ...: print("Stereo:", atom.GetChiralTag(), "Neighbours:",
[n.GetSymbol() for n in atom.GetNeighbors()])
   ...:
Stereo: CHI_UNSPECIFIED Neighbours: ['C']
Stereo: CHI_TETRAHEDRAL_CW Neighbours: ['O', 'C', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']
Stereo: CHI_TETRAHEDRAL_CCW Neighbours: ['C', 'C', 'C', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']
Stereo: CHI_TETRAHEDRAL_CW Neighbours: ['C', 'Cl', 'Br', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']
Stereo: CHI_UNSPECIFIED Neighbours: ['C', 'C']


-greg


On Wed, Feb 8, 2017 at 9:46 AM, James Davidson <j.david...@vernalis.com>
wrote:

> Hi Greg (et al.),
>
>
>
> Thanks for looking into it.
>
> And thanks to Paolo, who gave me a good workaround suggestion – which was
> to desymmetrise the spirocyclic centre by modifying the isotope on one of
> the neighbours.
>
> This is good for attended processing of single molecules, but not so good
> for unattended processing of unknown molecules…
>
>
>
> Reading in molecules with sanitize=False is a good start, but my first
> thought was then to do some sort of rSMARTS transform to automate the
> isomer assignment.
>
> It soon became apparent that this wasn’t the way to go – as abilities are
> limited with an unsanitised molecule(!).
>
>
>
> So I ended-up with the following:
>
>
>
> m3 = Chem.MolFromSmiles('O[C@H]1CC[C@]11CC[C@@](Cl)(Br)CC1',
> sanitize=False)
>
> for atom in m3.GetAtoms():
>
> print "Stereo:", atom.GetChiralTag(), "Neighbours:", [n.GetSymbol()
> for n in atom.GetNeighbors()]  # chiral centres currently intact
>
>
>
> # Find possible spirocentres
>
> for atom in m3.GetAtoms():
>
> if len(atom.GetNeighbors()) == 4 and atom.IsInRing() and
> atom.GetChiralTag() != 'CHI_UNSPECIFIED':
>
> # We have found a candidate spirocentre modify a neighbour at
> random
>
> first_neighbour = atom.GetNeighbors()[0]
>
> first_neighbour.SetIsotope(100)
>
> Chem.SanitizeMol(m3)  # Now we can sanitise
>
> test3_mols = summarise_conformers(m3)  # and generate the conformers (as
> before)
>
> sdf = Chem.SDWriter('test3.sdf')  # and write them out (but resetting the
> isotopes first)
>
> for mol in test3_mols:
>
> for atom in mol.GetAtoms():
>
> if atom.GetIsotope() == 100:
>
> atom.SetIsotope(0)
>
> sdf.write(mol)
>
>
>
>
>
> GIST is updated to include this:  https://gist.github.com/jepdavidson/
> fdfbf6366a17f4829de3d4de22f3b442
>
>
>
> Kind regards
>
>
>
> James
>
>
>
>
>
> *From:* Greg Landrum [mailto:greg.land...@gmail.com]
> *Sent:* 08 February 2017 03:45
> *To:* James Davidson
> *Cc:* rdkit-discuss@lists.sourceforge.net
> *Subject:* Re: [Rdkit-discuss] Stereochemistry issue for
> spirocycles/pseudochiral centres(?)
>
>
>
> Hi James,
>
>
>
> This is definitely a bug. The problem seems to be connected to the way
> what the RDKit calls "ring stereochemistry" is handled when there are spiro
> linkages.
>
>
>
> Here's the github issue: https://github.com/rdkit/rdkit/issues/1294
>
>
>
> I'll take a look.
>
>
>
> Best,
>
> -greg
>
>
>
>
>
>
>
> On Tue, Feb 7, 2017 at 8:32 PM, James Davidson <j.david...@vernalis.com>
> wrote:
>
> Dear All,
>
>
>
&

Re: [Rdkit-discuss] Stereochemistry issue for spirocycles/pseudochiral centres(?)

[James Davidson]

Hi Greg (et al.),

Thanks for looking into it.
And thanks to Paolo, who gave me a good workaround suggestion – which was to 
desymmetrise the spirocyclic centre by modifying the isotope on one of the 
neighbours.
This is good for attended processing of single molecules, but not so good for 
unattended processing of unknown molecules…

Reading in molecules with sanitize=False is a good start, but my first thought 
was then to do some sort of rSMARTS transform to automate the isomer assignment.
It soon became apparent that this wasn’t the way to go – as abilities are 
limited with an unsanitised molecule(!).

So I ended-up with the following:

m3 = Chem.MolFromSmiles('O[C@H]1CC[C@]11CC[C@@](Cl)(Br)CC1', sanitize=False)
for atom in m3.GetAtoms():
print "Stereo:", atom.GetChiralTag(), "Neighbours:", [n.GetSymbol() for n 
in atom.GetNeighbors()]  # chiral centres currently intact

# Find possible spirocentres
for atom in m3.GetAtoms():
if len(atom.GetNeighbors()) == 4 and atom.IsInRing() and 
atom.GetChiralTag() != 'CHI_UNSPECIFIED':
# We have found a candidate spirocentre modify a neighbour at random
first_neighbour = atom.GetNeighbors()[0]
first_neighbour.SetIsotope(100)
Chem.SanitizeMol(m3)  # Now we can sanitise
test3_mols = summarise_conformers(m3)  # and generate the conformers (as before)
sdf = Chem.SDWriter('test3.sdf')  # and write them out (but resetting the 
isotopes first)
for mol in test3_mols:
for atom in mol.GetAtoms():
if atom.GetIsotope() == 100:
atom.SetIsotope(0)
sdf.write(mol)


GIST is updated to include this:  
https://gist.github.com/jepdavidson/fdfbf6366a17f4829de3d4de22f3b442

Kind regards

James


From: Greg Landrum [mailto:greg.land...@gmail.com]
Sent: 08 February 2017 03:45
To: James Davidson
Cc: rdkit-discuss@lists.sourceforge.net
Subject: Re: [Rdkit-discuss] Stereochemistry issue for spirocycles/pseudochiral 
centres(?)

Hi James,

This is definitely a bug. The problem seems to be connected to the way what the 
RDKit calls "ring stereochemistry" is handled when there are spiro linkages.

Here's the github issue: https://github.com/rdkit/rdkit/issues/1294

I'll take a look.

Best,
-greg



On Tue, Feb 7, 2017 at 8:32 PM, James Davidson 
<j.david...@vernalis.com<mailto:j.david...@vernalis.com>> wrote:
Dear All,

I have hit what I think is a problem with stereochemistry perception/handling 
for certain types of pseudochiral and/or spirocyclic systems.
Basically I am observing that some types of input tetrahedral stereochemical 
information gets lost when an RDKit molecule is generated.
But I only realised this because I was wanting to generate conformers and was 
seeing stereochemical scrambling…

Anyway, an example with pictures will probably explain things better:
https://gist.github.com/jepdavidson/fdfbf6366a17f4829de3d4de22f3b442

Any help/advice appreciated.

Kind regards

James

__
PLEASE READ: This email is confidential and may be privileged. It is intended 
for the named addressee(s) only and access to it by anyone else is 
unauthorised. If you are not an addressee, any disclosure or copying of the 
contents of this email or any action taken (or not taken) in reliance on it is 
unauthorised and may be unlawful. If you have received this email in error, 
please notify the sender or 
postmas...@vernalis.com<mailto:postmas...@vernalis.com>. Email is not a secure 
method of communication and the Company cannot accept responsibility for the 
accuracy or completeness of this message or any attachment(s). Please check 
this email for virus infection for which the Company accepts no responsibility. 
If verification of this email is sought then please request a hard copy. Unless 
otherwise stated, any views or opinions presented are solely those of the 
author and do not represent those of the Company.

The Vernalis Group of Companies
100 Berkshire Place
Wharfedale Road
Winnersh, Berkshire
RG41 5RD, England
Tel: +44 (0)118 938 <tel:+44%20118%20938%20>

To access trading company registration and address details, please go to the 
Vernalis website at www.vernalis.com<http://www.vernalis.com> and click on the 
"Company address and registration details" link at the bottom of the page..
__

--
Check out the vibrant tech community on one of the world's most
engaging tech sites, SlashDot.org! http://sdm.link/slashdot
___
Rdkit-discuss mailing list
Rdkit-discuss@lists.sourceforge.net<mailto:Rdkit-discuss@lists.sourceforge.net>
https://lists.sourceforge.net/lists/listinfo/rdkit-discuss


__
PLEASE READ: This email is confide

Re: [Rdkit-discuss] Stereochemistry issue for spirocycles/pseudochiral centres(?)

[Greg Landrum]

Hi James,

This is definitely a bug. The problem seems to be connected to the way what
the RDKit calls "ring stereochemistry" is handled when there are spiro
linkages.

Here's the github issue: https://github.com/rdkit/rdkit/issues/1294

I'll take a look.

Best,
-greg



On Tue, Feb 7, 2017 at 8:32 PM, James Davidson 
wrote:

> Dear All,
>
>
>
> I have hit what I think is a problem with stereochemistry
> perception/handling for certain types of pseudochiral and/or spirocyclic
> systems.
>
> Basically I am observing that some types of input tetrahedral
> stereochemical information gets lost when an RDKit molecule is generated.
>
> But I only realised this because I was wanting to generate conformers and
> was seeing stereochemical scrambling…
>
>
>
> Anyway, an example with pictures will probably explain things better:
>
> https://gist.github.com/jepdavidson/fdfbf6366a17f4829de3d4de22f3b442
>
>
>
> Any help/advice appreciated.
>
>
>
> Kind regards
>
>
>
> James
>
> __
> PLEASE READ: This email is confidential and may be privileged. It is
> intended for the named addressee(s) only and access to it by anyone else is
> unauthorised. If you are not an addressee, any disclosure or copying of the
> contents of this email or any action taken (or not taken) in reliance on it
> is unauthorised and may be unlawful. If you have received this email in
> error, please notify the sender or postmas...@vernalis.com. Email is not
> a secure method of communication and the Company cannot accept
> responsibility for the accuracy or completeness of this message or any
> attachment(s). Please check this email for virus infection for which the
> Company accepts no responsibility. If verification of this email is sought
> then please request a hard copy. Unless otherwise stated, any views or
> opinions presented are solely those of the author and do not represent
> those of the Company.
>
> The Vernalis Group of Companies
> 100 Berkshire Place
> Wharfedale Road
> Winnersh, Berkshire
> RG41 5RD, England
> Tel: +44 (0)118 938  <+44%20118%20938%20>
>
> To access trading company registration and address details, please go to
> the Vernalis website at www.vernalis.com and click on the "Company
> address and registration details" link at the bottom of the page..
> __
>
> 
> --
> Check out the vibrant tech community on one of the world's most
> engaging tech sites, SlashDot.org! http://sdm.link/slashdot
> ___
> Rdkit-discuss mailing list
> Rdkit-discuss@lists.sourceforge.net
> https://lists.sourceforge.net/lists/listinfo/rdkit-discuss
>
>
--
Check out the vibrant tech community on one of the world's most
engaging tech sites, SlashDot.org! http://sdm.link/slashdot___
Rdkit-discuss mailing list
Rdkit-discuss@lists.sourceforge.net
https://lists.sourceforge.net/lists/listinfo/rdkit-discuss