Where the drug is a racemate, should we go ‘flat’?

Example: ketoconazole

Many drugs are racemates, as indicated by their INN document or FDA label. This presents us with a curatorial decision: should we represent both of the enantiomers as separate ligand entries, one ligand entry displaying the structure of one of the enantiomers, but representing the racemate, or a flat structure representing the mixture? And what structure should we link out to in PubChem and other resources?

Ketoconazole is a racemate of a 2R, 4S enantiomer and a 2S, 4R one. For this ligand and other racemates we have chosen to display a ‘flat’ structure, not specifying stereochemistry to represent the mixture. This follows a cross-check against PubChem to ensure the flat structure CID is supported by sufficient number of ‘same structure’ matches, and we also check that the references from which we have derived our biological activity data for the compound do not specify that they used a particular enantiomer in their experiments. Once we are sure of a consensus match for the flat structure on PubChem, and that our activity data can be mapped to a non-specific structure, the structure is curated and the corresponding CID added to the ligand entry. In these cases,  we have been sure to add contextual curators’ comments to our ligand entries and links to the CIDs representing the enantiomers. Where possible we try to ensure the links in our database links table also specify the flat structure, but where this is not possible we have indicated this in our comments.

N.B. There are cases where we have activity data for a particular chiral specification and for the racemate and in these instances we create ligand entries to represent both structures. In a subset of these cases, the single enantiomer is also a drug in its own right. For example: cetirizine and (R)-cetirizine. In a limited number of cases we have data for the racemate and both enantiomers and therefore maintain three separate ligand entries cross-linked by comments.

Special cases: active and inactive enantiomers 

Fluvastatin– racemic mixture with a more active enantiomer.

Fluvastatin was added to our database 3 years ago as part of a pilot project on enzyme pathway curation focusing on the lanosterol synthesis pathway. Unlike all the other statin drugs, the preparation of fluvastatin found in the marketed drug/INN-assigned structure is a racemate of two enantiomers: A ‘3R, 5S’ enantiomer (CID 446155), and a ‘3S, 5R’ enantiomer (CID 1548972). The following image is from the INN document for the drug:

(Image from: https://mednet-communities.net/inn/db/ViewINN.aspx?i=6547 , WHO MedNet, Accessed 02/7/14)

However, these two enantiomers do not have equal potency at the target (HMGCR), and it is the 3R, 5S enantiomer that is more active (PMID 16480934). A preparation of the compound with this particular chirality is used experimentally as a ‘standard’ against which new potential inhibitors of the enzyme are compared.

As discussed above, we normally display a ‘flat’ structure to represent racemic drugs. However, for fluvastatin the structure we chose to display represents the more active enantiomer found in the preparation of the approved drug, and we have annotated our ligand entry for fluvastatin with curators’ comments to justify our curatorial decision. PubChem users will note that if you look at the ‘Same, Isotopes’ link for the CID representing our ligand, you will find no less than 15 CIDs. These are permeated by the 2 stereocentres and the E/Z bond. We may write a future blog post to further discuss the complexity of curating representations of fluvastatin, and how this ligand compares to the other statin drugs.

Watch out for the next posts in this series, coming soon.

Contributed by Helen Benson

Our database now contains over 6500 ligands, spanning 7 chemical classes. An important part of our curation work is to ensure the chemical structures of these ligands are accurate through both careful curation of new ligands and the running of quality control checks on existing ligand structures. In a series of blog posts over the coming weeks we will discuss some case studies from our recent chemical curation work. These case studies were encountered when we worked on a dataset provided by the PubChem team, which involved quality control checks based on cross-referencing between our ligands and their corresponding CID-assigned entries on PubChem. The GtoPdb team are working on adding links to PubChem from all our ligand pages via CIDs therefore we are trying to ensure there is a consensus between the two resources on the structures of our ligands, and that in cases where a compound has been assigned multiple CIDs or is available in different preparations that our choice of curated structures and links, and where relevant supporting comments, reflects this. The topic of this post is discussed in further detail by our team member Chris Southan on his blog and recent poster.

Cross-referencing of lists of INN-assigned compounds between GtoPdb and PubChem revealed there were some mismatches in the specified stereochemistry, and in some cases nomenclature, of the INN-assigned compounds. In other cases, the structures for our ligands agreed with PubChem but the curated CIDs on the ligand pages pointed to PubChem entries with different stereochemistry, or in one instance with a slightly different structure. In order to resolve these differences, we completed cross-checking between our structures, those specified by FDA labels, INN documents and other resources, and the ‘consensus structures’ on PubChem. For readers unfamiliar with the term ‘consensus structure’, this refers to the CID entry on PubChem with the highest number of same structure matches in terms of SIDs for reported bioactivity data. We aim to link to the PubChem entry which has the highest number of same structure matches reported in bioactivity data references. However, in exceptional cases, the consensus structure on PubChem may not match our structure.

Following a review of each of our flagged ligand entries, we made a decision to either add a curators’ comment to our ligand entry explaining any differences between the resources, or where necessary make revisions to the chemical structure, ligand name or PubChem CID links included on the ligand page. This exercise revealed some ambiguities in several chemical structures and posed the challenge of deciding how they are best represented in databases. Some of the issues that arose during the course of this project were already familiar to the team while others were encountered for the first time during this exercise. We are working on devising protocols for our chemical curation methods which some of these case studies will help to define. As usual, we welcome feedback from our users, so please feel free to contact us with any comments you have on the series of posts to follow.

Contributed by Helen Benson