Thanks Greg and Andrew for the clarifications and tips, I will have another
look!
cheers
Fabian
On Wed, Mar 20, 2013 at 4:29 AM, Greg Landrum <[email protected]>wrote:
> Fabian,
>
> On Tue, Mar 19, 2013 at 2:05 PM, Fabian Dey <[email protected]> wrote:
> >
> > I started writing a RDKIT-python-script including Andrew Dalke's MCS
> > implementation (thanks by the way) for a ligand-based (MCS) alignment and
> > noticed some
> > odd things - which might also be due to my implementation. The idea of
> the
> > program is that given a template molecule and a library (both as SDF),
> the
> > MCS
> > is searched between the template and a particular library molecule. A new
> > conformation for the library molecule is generated using as a "coordinate
> > map"
> > the atoms identified in the MCS with the template (using
> > "EmbedMultipleConf(....)"). The conformations are optimized, redundancy
> is
> > removed and the most similar
> > conformations are written to a new SDF (full code at end mail , start
> with
> > "python MCSalign.py template.sdf library.sdf out.sdf ").
>
> nice idea. I like it!
>
> > The points I noticed:
> >
> > - after running "EmbedMultipleConf(....)" the atoms of the MCS are often
> not
> > aligned (reference vs. library compound) although I specified a
> coordinate
> > map (I also tried increasing the
> > force tolerance which did not help), and I have to do an additional
> > alignment for the correct superposition - is this to be expected?
>
> Yes. The coordinate map is used to provide distance constraints for
> the core. You need to do the alignment step to get the atoms in the
> right place.
>
> > - Sometimes when I use the same molecule as reference and library
> compound
> > (for testing purposes), the conformations do not match even after the
> > alignment ?
> > (e.g. ZINC-molecule http://zinc.docking.org/substance/33006049)
>
> I assume that you're doing the alignment and looking at the results
> before you call the force-field minimization? That would, of course,
> lead to problems.
>
> Another possible source of a mismatch is that the embedding process
> isn't perfect: the distance constraints you provide (the coordinates)
> are not necessarily perfectly satisfied in the conformation that's
> returned. What can help with this is to do a UFF optimization with
> added constraints that force the core atoms of the new conformation to
> match the core atoms in the reference molecule.
>
> You may find it useful to look at the the code in the function
> ConstrainedEmbed in $RDBASE/rdkit/Chem/AllChem.py. This does a
> constrained conformation generation for a molecule using a core as a
> reference structure. It doesn't do the MCS analysis, but you could
> pretty easily add that.
>
> > - in order to get a 1-1 correspondence of atom ids (to get the coordinate
> > map) I had to search the MCS-SMARTS match again against the original
> files
> > to
> > get the atom-ids - is there a more direct way to do this?
>
> There's not, as Andrew already answered.
>
> -greg
>
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