Discovery Platform

Domainex’s discovery platform enables rapid progression of drug discovery projects from novel target through to Candidate Drug by means of its Combinatorial Domain Hunting technology, LeadBuilder virtual hit screening software, and its integrated approach to medicinal and computational chemistry.

In a recent Nature Reviews Drug Discovery article (Pammolli et al., 2011), it was reported that the average drug discovery timelines within big pharma companies are 4½ years from target to Candidate Drug. However, Domainex is able to significantly reduce this time (by up to 30%) through use of its proprietary technologies, and its innovative and creative approach to discovery. So how does Domainex achieve this large time saving?

• Combinatorial Domain hunting (CDH): Domainex’s patented CDH technology enables the cloning and expression of soluble drug target protein domains in E. coli, followed by the identification of those constructs that are able to bind a ligand. This enables binding assays to be developed, facilitating hit identification studies. In only 3-4 months, all expressible ligand binding domains of a target protein are identified (from libraries of 20,000-100,000 constructs), enabling key rate limiting steps in early drug discovery to be easily overcome and resulting in large time savings over standard approaches.
• LeadBuilder in silico hit screening: Domainex is able to use information about the target protein and any known ligands, and/or similar information on related (i.e. homologous) proteins, to devise virtual hit screening strategies using its LeadBuilder in silico screening approach. This typically results in the identification of focussed screening sets of 1,000-10,000 hit-like compounds.  Selected compounds from this focus set can be rapidly screened using the developed label-free assays to give Hit compounds with the benefit of “lead-like” properties. This highly focussed approach, of using in silico screening to select compounds likely to hit the target, saves significant time over standard High-Throughput Screening approaches and can significantly increase hit rates. For instance, a typical HTS screen might have a hit-rate in a biochemical assay of 0.01-0.1%, whereas we often find that LeadBuilder affords screening sets with hit-rates of between 1-10% (based on unpublished internal and client data).
• Fragment-Based Hit Screening: Domainex has used its significant experience in drug discovery to develop a high quality unique collection of chemical fragments that will enable drug hunters to explore fragment space and efficiently identify a diverse range of starting points for discovery programs.

  The Domainex fragment collection has considerable advantages over other commercially-available collections of fragments, as it contains a more diverse range of potential interactions without any significant increase in lipophilicity or molecular weight. The consequence of this is that Domainex’s fragment collection is likely to reveal more potent hits. These hits can then be developed with or without an x-ray crystal structure.

  The hits identified from this new fragment collection can be efficiently developed into clinical candidates by Domainex’s experienced team of medicinal chemists and computational chemists.
  

Following the identification and validation of hits, Domainex's fully integrated approach to medicinal and computational chemistry enables the smooth progression to lead compounds and eventually to a Candidate Drug.

References

Fabio Pammolli, Laura Magazzini & Massimo Riccaboni (2011). The productivity crisis in pharmaceutical R&D. Nature Reviews Drug Discovery, 10, 428-438.

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