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I’ve been playing with InChIs these days quite a bit and have been quite suprised by the results that I got. The one thing that is very surprising indeed, is that the InChI - and therefore the InChIKey, should one want to use these to index a chemical compound database - one gets, seems to depend on the input format for the InChI generator.

After having seen some more InChI related things atthe BioIT World yesterday, I thought I’d have another go at some InChI stuff. And I was again quite surprised to what I found, and actually even more confused.

Here’s what I did:

I took two molecules from PubChem (diaisostereomers) cis- and trans-1,2-dihydroxy-cyclohexane (1,2-cyclohexanediol). I created InChIKeys for both of them, using different inputs. And not at all did I end up with two different InChIs for these two structures that were the same.

The SMILES and InChIKey from PubChem are the following:
cis-1,2-cyclohexanediol: C1CC[C@@H]([C@@H](C1)O)O - PFURGBBHAOXLIO-OLQVQODUSA-N
trans-1,2-cyclohexanediol: C1CC[C@H]([C@@H](C1)O)O - PFURGBBHAOXLIO-PHDIDXHHSA-N

I used the Standard InChI generator v1.2 released in January 2009 by the IUPAC, more specifically the Linux binary. Because this software doesn’t read SMILES, one has to convert the SMILES input molecules to SD files. This was done with OpenBabel and Pipeline Pilot. In addition, I used CML obtained from OpenBabel as input, too.

And here is what I obtained:

Now, this raises the following questions:

1. First of all, why do I not just get the same InChI for everything? Isn’t it supposed to canonicalize the structure to a fair extent (I know it does) and come up with the same InChI?
2. If there are different ways of getting a presumably valid InChI for a compound, which one should one take?
3. Why do I get the same InChI for different stereoisomers when the 3D coordinates come from OpenBabel, but not if the coordinates come from Pipeline Pilot? Is the 3D coordinate generation in OpenBabel the problem?
4. Why do I get the correst stereoinformation in the InChIKey when I use CML without any coordinates?
5. Why do I get a different hash for the connectivity part when I use CML without any coordinates? FWITZFBVZWAIRX instead of PFURGBBHAOXLIO?
6. And then, if CML without 3D coordinates gives the right stereochemistry in the InChI, why doesn’t 3D CML with coordinates from OpenBabel?
7. 3D CML from PipelinePilot coordinates also doesn’t get the stereochemistry part right; instead, there’s yet a different connectivity part DQQAEJAQEMHJBB.
8. Why should the stereochemistry come out right when 2D coordinates are used, but not if 0D coordinates are used?
9. Why not get InChIs directly from SMILES?

Any comments on this anybody? I seriously wonder.