Fragment-Based Hit Screening

What is FragmentBuilder?

 FragmentBuilder is Domainex’s fragment-based drug design (FBDD) platform. Starting from a target gene, Domainex deploys its 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 FBDD
  • Access to Domainex’s exclusive library:
    • Expertly selected
    • Diverse with good coverage of bioactive fragment space
    • Includes innovative SpiroChem fragments (greater complexity and 3D character)
  • Choice of primary screening methods available
  • Domainex can generate high resolution crystal structures of bound fragments
  • Modules can be accessed on their own or together to form a fully integrated service

 

High Quality Protein Supply

Domainex's highly experienced Protein Sciences team can generate crystallography-grade proteins in multi-mg quantities using E.coli and baculoviral-infected insect cell expression systems.

Our scientist can utilize standard bioinformatics/literature approaches or Domainex's proprietary technology Combinatorial Domain Hunting (CDH).

 

Exclusive fragment library

Domainex has curated a diverse collection of fragments.

  • Multi-parameter scoring function used to select compounds
  • Molecular fingerprints used and compared with ChEMBL fragments to ensure good coverage of bioactive space
  • Access to Spirochem fragments provides novel starting points
  • All compounds soluble at 1 mM in 1% DMSO

 

Fragment Screening

At the heart of the platform is screening of fragments by MicroScale Thermophoresis (MST, Nanotemper Technologies GmbH). This capillary-based, homogenous technology is able to quantify even weak binding events in a solution-based manner. The Domainex fragment collection can be screened in a matter of a few days to determine initial Kd values of fragment hits. Domainex has alternative screening methods available if required, such as HTRF, DSF and direct-binding mass spectrometry.

 

MST Advantages Over Alternative Methods

  • Minimal assay development
  • Little protein required
  • Solution-based, so no immobilization
  • Measure up to quaternary biological systems
  • Capture orthosteric and allosteric binders
  • Sensitive across the nM-mM range
  • A high throughput technique
  • Eliminates false positives early

 

X-ray Crystallography & SBDD

Domainex has the expertise to undertake crystal screens and through its access to the synchrotron at Diamond Light Source (Oxfordshire, UK) can obtain high-resolution structures of fragment hits bound to target proteins. These can then be used by computational and medicinal chemists at Domainex to guide an efficient fragment elaboration process.

 

Medicinal Chemistry and Computational Chemistry

Domainex has a team of computational and medicinal chemists with experience in FBDD. In addition, Domainex chemists understand the chemistry around their fragments. We can help you assess your fragment hits and optimize them to generate multiple lead series.

 

Orthogonal and Functional Testing

The Domainex Assay Biology team can establish competition assays to determine the mechanism of binding of identified screening hits and can use a range of orthogonal tests including:

  • Saturation Transfer Difference (STD) – NMR
  • Surface Plasmon Resonance (SPR)
  • Differential Scanning Fluorimetry (DSF)

 

Once the project has progressed, the team can run cellular assays to further profile novel compounds received from the medicinal chemistry team. In parallel, in vitro ADME assays are run on the most promising compounds to help identify tractable leads.

 

If you would like to find out more about fragment-based drug design including a case study detailing the identification and development of Domainex’s own drug candidate, DMXD-011 (a TBK1/IKKƐ inhibitor), please view our webinar.

View the webinar

 

Click here to download the brochure