All Cresset released fragment databases for Spark have been updated and are released alongside a new agrochemical-focused collection, ‘Agrochemical’. The update and expansion of the Spark fragment database portfolio gives access to millions of conformationally enriched fragments, providing an outstanding range of bioisosteres to search to generate novel ideas and advance your project with Spark, Cresset’s bioisostere replacement tool. Table 1 summarizes the fragment distribution for the new and updated databases.
Table 1. Total number of fragments, ‘Total frags’; and fragment distribution depending on the number connection points of the fragment, ‘Frags with 1/2/3/4 connection(s)’, or the connection point pattern, ‘Rings only frags’, for the Cresset released fragment databases for Spark.
| Database | Total frags | Frags with 1 connection | Frags with 2 connections | Frags with 3 connections | Frags with 4 connections | Rings only frags |
|---|---|---|---|---|---|---|
| Agrochemical1 | 10,976 | 2,245 | 3,973 | 3,204 | 1,554 | 235 |
| COD2 | 448,712 | 71,990 | 135,465 | 140,826 | 100,431 | 11,460 |
| CSD3 | 1,217,378 | 159,086 | 343,554 | 397,447 | 317,291 | 27,879 |
| ChEMBL4 | 2,160,380 | 452,482 | 769,882 | 617,913 | 320,103 | 32,094 |
| Commercial5 | 6,535,138 | 2,373,812 | 2,334,301 | 1,310,505 | 516,520 | 37,384 |
| SureChEMBL6 | 18,962,454 | 3,948,439 | 6,126,308 | 5,495,765 | 3,391,942 | 213,389 |
| Linkers – PROTAC – DB7 | 1,398 | 0 | 1,398 | 0 | 0 | 6 |
| Linkers – Enamine8 | 8,291 | 0 | 8,291 | 0 | 0 | 22 |
| VEHICLe9 | 170,467 | 57,528 | 61,586 | 37,217 | 14,136 | 35,206 |
The new and updated databases include ring-only fragments as well as fragments with 1 to 4 attachment points, which can be used in a variety of experiments including scaffold hopping, R-group exploration, fragment growing and linking, macrocyclization and crystallographic water replacement.
Additionally, circa 500K fragments with one connection point, derived from commercial reagents and suitable for R-group exploration experiments, are available and updated monthly.10 There are 23 ‘Reagents’ collections according to the transformation used to fragment the reagent, which correspond to widely used medicinal chemistry reactions.
The new ‘Agrochemical’ database
‘Agrochemical’, the new agrochemical-focused database, includes almost 11,000 conformationally enriched fragments derived from PubChem ‘Agrochemical’ category, relating to agrochemicals used in agriculture, including chemical fertilizers, pesticides and more.
Using an agrochemical-focused fragment database ensures that the results of your Spark experiment have a property profile suitable for applications in the agrochemical sector, as shown in Table 2.
Before the compound fragmentation, the PubChem compounds: i), ii) and iii) were prepared as follows:
i) 1,3 diones were enumerated and converted to the enolate form
ii) all procides (pro-pesticides) were removed
iii) the additional known transformations, a-c, were applied:
The physico-chemical properties for the fragments in the ‘Agrochemical’ database are summarized in Table 2 below.
Table 2. Properties of the fragments in the new ‘Agrochemical’ database for Spark. Number of fragments in the database, ‘Fragments’; number of conformations for a fragment, ‘NC’; number of heavy atoms of a fragment, ‘HA’; the fragment molecular weight, ‘MW’; and number of rotatable bonds ‘RB’.
| Database | Fragments | NC range | HA range | MW range | RB range |
|---|---|---|---|---|---|
| PubChem | 10,976 | 1 – 30 | 1 – 16 | 12 – 249 | 0 – 5 |
Use the new and updated Spark databases in your projects
All Cresset-created Spark databases are available to all Spark users, and can be downloaded from the ‘Database Updater’ in the Spark tab in Flare, as shown in Figure 1 and 2.
Figure 1. Updated fragment and reagent databases can be downloaded from the Database Updater, filtering for the ‘Updates’ category on the top-right corner.
The new ‘Agrochemical’ database can also be downloaded from the ‘Database Updater’, Figure 2.
Figure 2: The new ‘Agrochemical’ database can be downloaded from the Database Updater, filtering for the ‘New’ category on the top-right corner.
If you are using Spark integrated into Flare, calculations using with the ‘Ligand Similarity’ score method (based on the Cresset XED force field)11 will use a distance-dependent dielectric, for consistency with calculations performed on proteins. For consistency, this new release of Spark fragment and reagent databases was also created using a distance-dependent dielectric.
Using the updated collections with stand-alone Spark will require a Spark 10.8 version or higher. Please contact us to request the download links for the latest version. Note from Spark 10.8 onward, field point calculations on native Spark will use a distance-dependent dielectric as well, for consistency with Spark integration into Flare.
Try Spark on your projects
If you’re currently not using Spark, but would like to try it, contact us to find out how Spark can impact your project.
References
- https://pubchem.ncbi.nlm.nih.gov/
- http://www.crystallography.net/cod/
- https://www.ccdc.cam.ac.uk/solutions/csd-system/components/csd/
- https://www.ebi.ac.uk/chembl/
- https://www.emolecules.com/products/screening-compounds
- https://ftp.ebi.ac.uk/pub/databases/chembl/SureChEMBL/
- http://cadd.zju.edu.cn/protacdb/
- https://enamine.net/building-blocks-mob/linkers-for-linkerology
- Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. Heteroaromatic Rings of the Future. J. Med. Chem. 2009, 52 (9), 2952–2963 https://doi.org/10.1021/jm801513z1
- https://www.emolecules.com/products/building-blocks
- Vinter, J.G. Extended electron distributions applied to the molecular mechanics of some intermolecular interactions. J Computer-Aided Mol Des 1994, 8, 653–668. https://doi.org/10.1007/BF00124013