Medicinal and Computational Chemistry

Domainex has a team of highly skilled chemists experienced in FBDD who will optimise your fragment hits. Domainex and SpiroChem chemists understand the chemistry around their fragments and together can quickly synthesise analogues/elaborated compounds. Domainex has developed an efficient process for fragment hit expansion.

FACE (Fragment Analogues for Chemical Evaluation):

-200,000 commercially-available compounds that meet our fragment criteria.

 

NICE (Number of Interesting Chemical Entities):

-2 million lead-like commercially-available compounds.

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.

To view a successful fragment optimisation programme, please see our joint publication with Professor Terry Rabitts at the University of Oxford.

Figure 1: Crystal structure of KRASQ61H-GppNHp and Abd-7 (Kd 51 nM), a small molecule inhibitor developed at Domainex, bound in a pocket close to the switch region.1

Reference:
1. Quevedo et al; Nature Communications, 2018, 9, 3169.

Orthogonal & 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.