Domainex

Domainex is able to offer seamless support of its clients' DMPK testing requirements within its laboratories in Cambridge. Its capabilities include a wide range of in vitro tests, including:

• Physico-chemical properties
  
  • LogD
    
  • Solubility in PBS or biological fluids
    
  • Stability in PBS or biological fluids
    
• Metabolic stability
  
  • Metabolic stability in liver microsomes, S9 fraction
    
  • Metabolic stability in cryopreserved hepatocytes
    
  • Metabolic stability in other tissues and fluids (as % turnover, half life or intrinsic clearance)
    

Via its closely located partner, Pharmidex, Domainex is also able to offer the full range of ADMET assays; as listed below. Domainex and Pharmidex have built up an excellent working relationship over a number of years and both companies work together to ensure speed and efficiency at all stages of a client's discovery programme.

Pharmidex's offering includes, but is not limited to:

• Blood distribution and protein binding
  
  • Plasma protein binding - human & most species
    
  • Blood partitioning - human & most species
    
  • Tissue partitioning human & most species
    
  • Blood to brain partitioning - human & most species (fraction unbound)
    
• Cell Permeability and transporter interactions
  
  • Cell permeation - passive and Pgp mediated (MDR/MDCK)
    
• CYP interactions
  
  • Inhibition in singly-expressed human P450 inhibition
    
  • Inhibition of Human P450 in microsomes (probe drugs via LC-MS/MS)
    
  • Time dependent inhibition of human P450s
    
  • Induction- Human P450 induction in hepatocytes
    
  • Reaction Phenotyping -Human P450Â isoform specific metabolism reactive metabolism glutathione trapping
    
  • Metabolite identification in biological samples

FragmentBuilder - identifying higher quality lead compounds

If you have a pure and well-characterised protein, fragment screening offers a practical and cost-effective alternative to traditional high-throughput screening methods. Our high-throughput fragment-based drug discovery services are designed to provide you with high quality lead compounds at a speed and quality not matched by our competitors.

Exclusive fragment library

Your search needs to be thorough and efficient. That’s why the fragment-based drug discovery team at Domainex have used their significant experience in drug discovery to build their own high quality and unique collection of chemical fragments. The 1,000 fragment library has been designed to provide good coverage of the ‘ideal fragment space’. The diverse range of pharmacophores make it the ideal starting point for your next drug candidate.

Innovative screening

Domainex is the first contract research organisation in the UK to offer automated MicroScale Thermophoresis (MST) as part of our fragment-based drug discovery services. The high-throughput technique quantifies molecular interactions and structural dynamics, to present binding affinity results in just a few minutes. There are many reasons we think MST offers many advantages over alternative molecular interaction assay methods:

It’s quick

• Fast, flexible assay set up and a capability of making 400 measurements per hour
  

It’s sensitive

• Measurements are carried out in solution, meaning free choice of assay buffer systems and no surface immobilisation of target proteins
  
• Broad concentration range (from pM to mM)
  
• Live detection of absorption, aggregation and precipitation effects
  

It’s efficient

Small sample consumption (fragment screening using as little as 400µg of protein)
Just the beginning…

We’re confident that our exclusive fragment library and screening techniques will provide you with high quality hit compounds. But that is just the beginning. We can identify soluble domains using our proprietary Combinatorial Domain Hunting platform, and transform hit molecules into clinical candidates using the skills and experience of our medicinal and computational chemists.

Expertise in computational chemistry can significantly improve the efficiency of drug discovery, especially when it is well integrated with a dynamic medicinal chemistry team, as at Domainex. The ongoing development of theoretical models, based on the most up-to-date results, ensures that scientists have the best opportunity of designing relevant novel chemical entities. Domainex offers expertise in a range of computational chemistry solutions including:

Hit finding through our proven LeadBuilder approach

This includes the virtual screening of our Lead-like (NICE) database using a combination of pharmacophore-based and structure-based techniques (such as docking). See 'LeadBuilder' for more information.

Scaffold hopping

Through techniques such as de novo design and similarity searching, we are able to identify patent-busting scaffolds and compounds.

Ligand-Based Drug Design

Using the existing knowledge of known active compounds, we can generate information-rich models containing pharmacophore features that are common to many of the known ligands. These models can then be used in Virtual Screening to search a database of compounds.

Structure-based drug design (SBDD)

By visualizing and analyzing models based on structural data, we are able to assist scientists in the rational design and development of novel molecules that bind to the biological target of interest.

Domainex is able to establish useful homology models for drug targets where there is no existing crystal structure information available, or to complete structural studies in order to resolve novel structures.

By visualizing and analyzing models based on structural data, we are able to assist scientists in the rational design and development of novel molecules that bind to the biological target of interest.

Domainex is able to establish useful homology models for drug targets where there is no existing crystal structure information available, or to complete structural studies in order to resolve novel structures.

Domainex provides high-quality medicinal chemistry services and synthetic chemistry services that efficiently progress drug discovery projects from hit identification through lead generation and optimization, to the nomination of effective drug candidates. Our medicinal chemists have extensive experience in developing drug candidates against a broad range of target disease indications, which has provided us with one of the best track records in the industry; with an average of one candidate drug nominated every year!

Supported by our computational chemistry expertise and BioassayBuilder platform, Domainex will design and provide a medicinal chemistry programme tailored to your specific requirements. Our “every compound counts” philosophy means that we take into account all the relevant properties including biological activity, selectivity, pharmacokinetic (i.e. ADME) and toxicology properties in parallel, as well as patentability, in the design of your compounds.

Domainex can help with all aspects of hit-to-candidate activities including:-

• Hit Identification
  
• Hit to Lead
  
• Lead Optimisation
  
• Back-up Candidate Identification
  
• Development of compounds for oral, inhaled or parenteral administration
  

Domainex has an established track record in a diverse range of target and ligand classes, including:-

• Enzymes such as kinases, proteases, etc.
  
• Protein-protein interactions
  
• Peptidomimetics
  
• Ion channels
  
• HDACs
  
• DUBs
  

Our medicinal chemistry services can be integrated with our computational chemistry, structural biology, protein expression, ADMET/PK and BioassayBuilder services to provide you with a comprehensive drug discovery solution.

BioassayBuilder is a suite of bioassay services, from protein expression to characterisation of pre-clinical candidates. Our team of experienced molecular, assay and cell biologists are able to support you in a way precisely adapted to your needs. Whether you have specific requirements or are looking for a partner to provide a full range of support, covering for instance:

• Protein expression
  
• Assay development
  
• Compound screening
  
• MOA characterization
  
• Phenotypic profiling
  
• Off-target safety assessment or determination of potential PD markers
  

Our specialists will work with you from initial discussions through to project completion and be ready to adapt to your changing needs and nature of the results as they emerge.

Key features & deliverables of the Domainex BioassayBuilder services are:

• Highly customised service to meet your needs
  
• Ability to offer a complete screening cascade
  
• Careful stewardship with minimised consumption of your compounds
  
• Quality assurance: pre-set assay acceptance criteria
  
• Provision of high quality data, proteins or assay systems in a timely manner
  
• Ownership of test results assigned to you
  
• Ability to troubleshoot, generate ideas and be flexible
  
• Can be efficiently linked to medicinal chemistry

The availability of sufficient protein of good quality can be rate limiting for many drug discovery programmes, as a lack of target protein supply can hamper the ability to establish hit screening assays and to complete structural studies.

As part of our BioassayBuilder platform, Domainex's biology team is able to clone, express and purify your proteins of interest and can produce protein at the required levels for ongoing biochemical compound screening or structural studies, extremely quickly, whether in E. coli or insect cells, up to the 12 L or 5 L scale respectively.

Domainex's scientists' experience is broad and they have successfully provided protein for a wide range of drug discovery programmes, including, but not limited to: kinases, proteases, protein-protein interactions, protein methyltransferases and demethylases. In cases where standard bioinformatics or literature-informed molecular biology approaches are not appropriate, Domainex is able to offer its proprietary high throughput cloning technology, Combinatorial Domain Hunting (CDH), which quickly enables the screening of 30,000-100,000 different gene constructs of a given target protein.

Hit Identification Services

Pharmacology Services

Pharmacology & Toxicology Services

Protein Services

Structural Biology Services

Biochemistry & Molecular Biology Services

Biology Services