Skip to main content

Bioisostere Discovery

Here is an old, old use case we developed for StARlite, this one looks at using data contained within StARlite to discover bioisosteres - a functional group replacement that preserves activity while improving other properties, such as metabolism, patentability, solubility etc. The algorithm exploits the useful 'data structure' of StARlite, in that compounds are typically entered in the literature/database as clusters of synthetically related compounds (i.e. they typically share late stage intermediates in their production), and therefore there are often reasonably straightforward ways to synthetically access these related compounds. Secondly, again because of the structure of the data, there are often equivalent assays to compare (same assays, done under the same conditions, by the same people), and so this removes one important variable from any further analysis (this is performed using the simple heuristic of only comparing quantitative data from the same StARlite doc_id).

Here is some (truly appalling, almost prose it has been noted) pseudocode, in which one wants to find possible replacements for a particular Functional Group (for example, a nitro, a vinyl halide, a sulphonamide, etc.)

1. Search StARlite for the all examples of the Functional Group
2. Identify all fragments that these Functional Groups are attached to (call these 'Contexts')
3. Search StARlite for all Contexts, then identify the corresponding Replacement Functional Groups
4. Build a table of Replacement Functional Groups and the count the frequency of each type of interchange (this frequency list is pretty useful in its own right)
5. Retrieve quantitative values of binding energy difference (using endpoints such as IC50, Ki, Kd, etc., constraining the comparison to the same assay_ids from the same doc_ids
6. Use these binding energy differences to compute an expectation value for the binding energy difference between the Functional Group and the Replacement Functional Group

So a good bioisostere would preserve (or improve) binding energy, these are then pretty easy to identify from the tables generated above. Of course, with the multiple end points stored in StARlite, and the generality of the approach, the same basic workflow can be used to identify functional group replacements that can improve half-life, solubility, logD, etc., etc.

Here is an old slide of a real case, the replacement of a carboxylic acid with other functional groups. Hopefully, with the background above, the figure is self explanatory....

The picture used in the header of the post is from the excellent and very amusing B'eau Bo D'Or blog, and I think perfectly illustrates bioisosterism - albeit in a context that is completely opaque to anyone not steeped in the 70's and 80's popular culture of the United Kingdom.

Comments

Popular posts from this blog

New SureChEMBL announcement

(Generated with DALL-E 3 ∙ 30 October 2023 at 1:48 pm) We have some very exciting news to report: the new SureChEMBL is now available! Hooray! What is SureChEMBL, you may ask. Good question! In our portfolio of chemical biology services, alongside our established database of bioactivity data for drug-like molecules ChEMBL , our dictionary of annotated small molecule entities ChEBI , and our compound cross-referencing system UniChem , we also deliver a database of annotated patents! Almost 10 years ago , EMBL-EBI acquired the SureChem system of chemically annotated patents and made this freely accessible in the public domain as SureChEMBL. Since then, our team has continued to maintain and deliver SureChEMBL. However, this has become increasingly challenging due to the complexities of the underlying codebase. We were awarded a Wellcome Trust grant in 2021 to completely overhaul SureChEMBL, with a new UI, backend infrastructure, and new f

Improved querying for SureChEMBL

    Dear SureChEMBL users, Earlier this year we ran a survey to identify what you, the users, would like to see next in SureChEMBL. Thank you for offering your feedback! This gave us the opportunity to have some interesting discussions both internally and externally. While we can't publicly reveal precisely our plans for the coming months (everything will be delivered at the right time), we can at least say that improving the compound structure extraction quality is a priority. Unfortunately, the change won't happen overnight as reprocessing 167 millions patents takes a while. However, the good news is that the new generation of optical chemical structure recognition shows good performance, even for patent images! We hope we can share our results with you soon. So in the meantime, what are we doing? You may have noticed a few changes on the SureChEMBL main page. No more "Beta" flag since we consider the system to be stable enough (it does not mean that you will never

ChEMBL brings drug bioactivity data to the Protein Data Bank in Europe

In the quest to develop new drugs, understanding the 3D structure of molecules is crucial. Resources like the Protein Data Bank in Europe (PDBe) and the Cambridge Structural Database (CSD) provide these 3D blueprints for many biological molecules. However, researchers also need to know how these molecules interact with their biological target – their bioactivity. ChEMBL is a treasure trove of bioactivity data for countless drug-like molecules. It tells us how strongly a molecule binds to a target, how it affects a biological process, and even how it might be metabolized. But here's the catch: while ChEMBL provides extensive information on a molecule's activity and cross references to other data sources, it doesn't always tell us if a 3D structure is available for a specific drug-target complex. This can be a roadblock for researchers who need that structural information to design effective drugs. Therefore, connecting ChEMBL data with resources like PDBe and CSD is essen

ChEMBL & SureChEMBL anniversary symposium

  In 2024 we celebrate the 15th anniversary of the first public release of the ChEMBL database as well as the 10th anniversary of SureChEMBL. To recognise this important landmark we are organising a two-day symposium to celebrate the work achieved by ChEMBL and SureChEMBL, and look forward to its future.   Save the date for the ChEMBL 15 Year Symposium October 1-2, 2024     Day one will consist of four workshops, a basic ChEMBL drug design workshop; an advanced ChEMBL workshop (EUbOPEN community workshop); a ChEMBL data deposition workshop; and a SureChEMBL workshop. Day two will consist of a series of talks from invited speakers, a few poster flash talks, a local nature walk, as well as celebratory cake. During the breaks, the poster session will be a great opportunity to catch up with other users and collaborators of the ChEMBL resources and chat to colleagues, co-workers and others to find out more about how the database is being used. Lunch and refreshments will be pro

ChEMBL 34 is out!

We are delighted to announce the release of ChEMBL 34, which includes a full update to drug and clinical candidate drug data. This version of the database, prepared on 28/03/2024 contains:         2,431,025 compounds (of which 2,409,270 have mol files)         3,106,257 compound records (non-unique compounds)         20,772,701 activities         1,644,390 assays         15,598 targets         89,892 documents Data can be downloaded from the ChEMBL FTP site:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/ Please see ChEMBL_34 release notes for full details of all changes in this release:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/chembl_34_release_notes.txt New Data Sources European Medicines Agency (src_id = 66): European Medicines Agency's data correspond to EMA drugs prior to 20 January 2023 (excluding vaccines). 71 out of the 882 newly added EMA drugs are only authorised by EMA, rather than from other regulatory bodies e.g.