To support research and development of Targeted Protein Degradation (TPD) therapeutics, four new linker databases have been released for Spark, Cresset’s scaffold hopping and bioisostere replacement tool. The new databases were created from the PROTAC-DB library,¹ from the Tingjun Hou group; and the Linkers for Linkerology collections from Enamine.²

Figure 1: The new ‘Linkers’ databases are available to all Spark customers and include over 9,500 linkers suitable for TPD research.

In a recent article, we have explored the application of a Spark scaffold hopping experiment to a degrader (Figure 2) using the default Spark databases (‘VeryCommon’, ‘Common’ and ‘ChEMBL_common’); as well as the newly released ‘Linkers’ databases: ‘PROTAC-DB’, ‘Enamine Stock Linkers’, ‘Enamine MADE Aromatic’, and ‘Enamine MADE Aliphatic’.

The results confirm the benefit of using linker-focused Spark databases in support of TPD research. While only two of the known linkers were found among the 161,854 searchable fragments in the default Spark databases, the search performed on only 9,672 fragments in the new databases retrieves 8 out of the 10 known TPD linkers.

The new databases contain fragments specific for designing linkers of degraders. Accordingly, they are a very promising computational tool for efficient linker design, including the exploration of empty space between the ligand targeting the protein of interest, and the ligand targeting the E3 ligase.

Figure 2. Degrader AK-2292 from Kaneshige, A. et al.³ The linker is highlighted in blue in both the 2D (left) and 3D (right) representations (PDB:7TVA).

The new ‘Linkers’ databases

The new linker databases overall include over 9.6K known and commercial TPD linkers derived from experimental sources. Their properties are summarized in Table 1 below.

Table 1: Properties of the new ‘Linkers’ databases for Spark. Fragments: number of fragments in the database; NC: number of conformations for a fragment; HA: number of heavy atoms of a fragment; MW: the fragment molecular weight; RB: number of rotatable bonds.

Overall, the fragments in the new ‘Linkers’ databases are characterized by a significantly larger MW and RB range with respect to those included in the standard Spark databases, which is reflected in the much larger number of conformations generated for the largest fragments.

Use the new Spark ‘Linkers’ databases for your TPD projects

The new linker databases expand the already large portfolio of currently released databases for Spark, derived from commercially available screening compounds, literature reports, patents, commercial reagents, small molecule crystal structures, and theoretical ring systems. Spark databases provide an outstanding range of millions of bioisosteres to search, to generate novel ideas and advance your project.

The new linker databases are immediately available to all Spark users and can be downloaded from the Spark Database Updater (Figure 3). However, searching the TPD-focussed databases requires an updated version of Spark V10.7.1, which we have released alongside the linker databases. Please contact us to request the download links for the Spark V10.7.1.

Figure 3: The new ‘Linkers’ databases are available to all Spark customers from the Spark Database Updater. Searching these databases requires an updated version of Spark V10.7.1. Contact us to request the updated download links.

Existing customers with no interest in TPD linker design and the use of the new ‘Linkers’ databases for Spark can continue using the previously released version, Spark V10.7.

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If you’re currently not using Spark, but would like to try it, request an evaluation to find out how Spark can impact your project.

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References

1. http://cadd.zju.edu.cn/protacdb/
2. https://enamine.net/building-blocks-mob/linkers-for-linkerology
3. Kaneshige, A. et al. J Med Chem 2023, 66, 4, 2717–2743