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During the early phases of drug discovery, the value (both from a therapeutic perspective and an intellectual property perspective) is determined by the identification of one or more classes of compounds able to modulate the activity/phenotype of the biological model system under investigation. Several approaches have been used, including: rational design, serendipitous discoveries, optimization of natural ligands and screening of libraries of molecules. The screening paradigm, i.e. the idea of randomly screening large compound libraries covering the chemical space as best as possible, was enabled in the late 80s by the advent of automation in research laboratories, starting the era of high throughput screening (HTS).

The use and success of HTS approaches has been debated in the past decades. Nowadays, it is generally believed that two factors are key to the success of a screening campaign:

  • The quality and coverage of the screening library
  • The quality and validation of the screening assay

We have a diverse collection of c. 320,000 compounds with focused sub-collections. The library periodically undergoes quality control on a subset of compounds. So far, the great majority of the molecules was found to be > 90% pure. Tractable hit molecules were found in several dozens of screening campaigns run so far, including tough targets like protein-protein interactions.

In terms of assays, we strongly believe that the validity of the readout comes first as opposed to the throughput. To this aim we employ several pre-screen orthogonal technologies, both biochemical and cellular, for increasing the confidence on the screening readout. We have experience in biochemical and cell based HTS:

  • Biochemical HTS
    • Enzymatic (e.g. kinases, phosphatases, deacetylases, acetyl-transferases, metabolically active enzymes, deglycosylase, proteases, etc.)
    • Protein-protein interaction involving peptide-protein complexes, but also large macromolecular complexes.
  • Cell based HTS
    • Target/phenotype detection via homogeneous immunoassays (e.g. TR-FRET or Alpha)
    • Reported based assay (both transcriptional and non-transcriptional)
    • Imaging based with primary cells (via plate based cytometry or high content screening)
    • Viability/proliferation on cells or even entire organisms (e.g. parasites)

Both our compound management and screening platform take advantage of fully integrated robotics that allows the handling of tens of thousands of compounds in high density format, such as 384 and 1536 well/plates.

HTS is a mature technology which nonetheless has shown both weakness and strength. We are convinced that, although a successful translation from hit identification to pre-clinical candidate is often challenging, a thorough approach at the hit identification step is vital for increasing the probability of success of a drug discovery program

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