Direct-to-Biology (D2B)

Which Chemistry? Which Programme?

Early publications that described the Direct-to-Biology approach used amide couplings for Targeted Protein Degraders (TPDs). However, the field has only continued to grow since then. Multi-step transformations, and palladium catalysis, are now well precedented in the literature and by Domainex. It’s not just TPDs either: covalent and reversible fragments, molecular glues and traditional small-molecule programmes have all been described now. 

Speak to our experts to find out how a personalised D2B campaign can accelerate your programme, and take advantage of:

• Expert computationally guided library design using molecular modelling and in silico property predictions
• Customised assay development by our team of highly skilled biologists
• Rapid synthesis and SAR generation by our D2B chemistry experts
• Generation of further data on your molecules in addition to bioactivity data including measurement of early druglike properties such as chromatographic LogD (ChromLogD) and EPSA - from the same screening sample

D2B Compatibility Tests

We are proud of our rigorous D2B workflow which has a focus on ensuring quality, as well as speed. That’s why each of our D2B campaigns begin with a compatibility test to ensure we achieve a robust data set, before embarking on the D2B synthesis. 

To assist in the selection of the right assay technology for your programme, we’ve tested commonly used techniques to get an early insight that goes beyond the available literature (Table 1).

Table 1. Assessment of the compatibility of different D2B reactions with different assay formats (NT = not tested, CuAAC = Copper Catalysed Azide-Alkyne Cycloaddition).

Our Case Studies

Our drug discovery follows the data, and our case studies in Direct-to-Biology lead the way globally: 

• Using our Partial PROTAC toolbox: Targeted Protein Degrader Toolbox
• Fast fragment follow up for Adenosine A2a: Using Direct-to-Biology in a Spectral Shift-PoLiPa Platform to Enable Fast Fragment Follow-Up for Adenosine A2a Antagonists
• D2B enabled covalent fragment screening: case study coming soon

Domainex’s D2B Workflow

Up to 384 compounds can be generated in a single plate and screened using the workflow below:

• Plate-based reaction optimisation is undertaken prior to D2B to ensure workflow efficiency and to minimise reagent usage.
• Utilising this process, 1,000s of compounds can be synthesised and screened in less than 1 month
• Automated QC and analysis, using UPLC MS, is conducted to allow a heat-map overview to be produced to assess the quality of each plate (see Figure 1)
• Hits can be observed even when a relatively low sample purity is observed.

Figure 1. Automated QC analysis & evaluation in degradation assays. (A) A heat map of compound purity (automated UPLC-MS) generated by PyParse, (B) D2B assay readout for 4 compounds; levels of cellular protein degradation (Nano-Glo^®) and automated Western blotting showing concentration dependent TPD.

D2B combines plate-based chemistry with rapid screening, synergistically enhancing the efficiency and success of drug discovery. These methods allow researchers to explore rapidly chemical space, identify hits, validate their biological activity, gain early insights into mechanism of action and asses the ADME properties, ultimately streamlining the development of novel and effective therapeutics. By embracing these cutting-edge techniques, Domainex will accelerate your drug discovery programmes and help you to bring life-changing medicines to patients more efficiently and effectively.