Domainex's Drug 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 for the expression of protein for structural studies and assay design, LeadBuilder virtual and fragment-based approaches to hit identification, 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% (9-12 months from target to lead, 2 years for lead optimization) 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 and can be produced in relatively large amounts for use in structural studies and/or assay development. This enables activity or 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 activity or binding 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).
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.
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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