FragmentBuilder is Domainex’s Fragment-Based Drug Discovery (FBDD) platform that enables us to rapidly identify hits against your chosen target. Starting from a target gene, Domainex deploys its FBDD expertise in protein science, assay biology and medicinal chemistry to discover tractable, patentable leads cost-effectively.
Why choose FragmentBuilder?
- Domainex has a proven track record in fragment-based drug discovery (FBDD)
- It includes access to the exclusive Domainex fragment library:
- Expertly selected
- Good coverage of bioactive fragment space
- Includes innovative SpiroChem fragments (giving greater diversity and sp3 character)
- A range of primary screening techniques are established
- Our X-ray crystallography platform will support fragment elaboration in real time
- A fully integrated service is available or individual modules can be selected and tailored to your needs
High-Quality Protein Supply
Our highly experienced Protein Science team can prepare crystallography-grade proteins for you in multi-milligram quantities using standard bioinformatics and literature-informed approaches or, if required, by deploying our proprietary technology Combinatorial Domain Hunting (CDH).
Diverse Fragment Collection
Domainex has assembled a unique collection of over 1000 diverse fragments, available for immediate screening against your target.
- A multi-parameter scoring function was employed for compound selection
- Molecular fingerprints were generated and compared with those of ChEMBL fragments to ensure good coverage of bioactive space
- Access to sp3-rich fragments from SpiroChem provides novel starting points
- All compounds are soluble at 1mM in 1% DMSO
Our library adheres to the key principles of fragment-based drug discovery (FBDD): low molecular weight, a limited number of hydrogen bonding groups, a balance of polarity and lipophilicity, and a small number of rotatable bonds.
Screening is a key component of the FragmentBuilder platform, and naturally Domainex uses methods that have a good track record of being able to detect the relatively weak binding of fragments. Typically, we aim to deploy the NanoTemper instrumentation which uses thermo-optical measurements (MicroScale Thermophoresis (MST) and Temperature Related Intensity Change (TRIC)) to detect ligand binding, as this has a number of advantages over other screening techniques, as described in our webpage on Biophysics. However, we can use a range of alternative biophysical screening methods if these are required, and we have also found HTRF to be a robust and very useful technique in some cases (see our white paper here). One of the advantages of the NanoTemper and HTRF methods is that it is generally straightforward to use saturating concentrations of competitive ligands to bias the fragment hits towards alternative binding sites, and this can often be attractive to our clients.
After the Screen
With confirmed fragment hits in hand, the next step is to increase their affinity and establish some initial structure-activity relationships. We do this through a combination of targeted acquisition of related compounds selected from our databases of commercially available compounds, and the synthesis of well-designed compound arrays around the fragment hits. The Domainex team of skilled medicinal and computational chemists are highly experienced in fragment-based drug discovery (FBDD) and know how to do this. They understand the chemistry around our fragments and can quickly synthesise analogues and elaborated compounds to increase their affinity. At the same time, we recommend that our structural biologists obtain high-resolution crystal structures of fragments bound to the target of interest, which can help guide this elaboration process.
For a FBDD case study please see: G9a: A FBDD programme to identify lysine methyltransferase inhibitors for the treatment of cancer.