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Natural products have long been a major source of new medicines. About 50% of the drugs introduced to the market in the last 20 years trace their origin to compounds derived from nature. A similar impact has been experienced in animal health and agrochemical discovery.
Assay development and hit identification from natural product libraries
BioFocus DPI (or clients) can screen the natural product fractions, screen our collection of over 500 isolated natural compounds with known structures, or screen our focused libraries based on natural product scaffolds. At BioFocus DPI, we have experience in developing robust, reliable assays suitable for HTS of natural product subfractions for a broad range of target classes - notably GPCRs, kinases, proteases and ion channels. With a track record of performing hundreds of drug discovery projects on a wide range of target classes, we have accumulated significant expertise in various therapeutic areas using a number of assay formats. These formats include enzyme activity, receptor binding and functional receptor assays as well as protein-protein interaction studies and eukaryotic and prokaryotic cell-based assays. Once a suitable assay has been established, subfractions or pure natural compounds are screened using highthroughput and ultra-high throughput technologies. After data is processed by state-of-the-art tools, hits are ranked according to activity, selectivity, sample polarity and microbial source. This robust screening approach results in primary hits with a high confidence level, generating quality compounds for hit follow-up and lead finding.
Selected subfractions undergo one additional fine fractionation step, which delivers samples suitable for dereplication. Active fine fractions are analyzed by LC-MS and the analytical data is used to identify known compounds by comparison with our extensive in house and relevant commercial databases.
New compounds selected after dereplication are refermented and isolated in mg amounts for structure elucidation and biological profiling. Using NMR and other analytical procedures, we determine the structure of hit molecules generated from a natural compound screen within a few days. Our natural product isolation group is able to (re)supply gram amounts of pure, active compounds for profiling, animal studies and semi-synthetic derivatization. Using our production-scale fermentation capacity and preparative HPLC equipment, we are able to purify tens of grams of natural compounds.
Our synthesis team is particularly skilled in the semisynthetic modification and optimization of natural product leads (solution and solid phase parallel synthesis) including the generation of focused libraries around natural scaffolds through parallel synthesis.
Case studies
Hit identification from subfractions
A Ser/Thr-kinase screen of 10,000 subfractions delivered
330 hits. After hit validation and selectivity testing, 40 subfractions were fine fractionated. The program resulted in new and known compounds from several structural classes, which are currently in the hit-to-lead phase, e.g. a known compound that has not yet been described as kinase inhibitor and a new kinase inhibitor scaffold.
Lead optimization of natural compounds
Fredericamycin A (FMA) from Streptomyces griseus was identified as starting point for a novel anti-tumor agent.
Following strain optimization and production of the starting material, the compound was converted into 300 derivatives through a semi-synthetic process. Screening against an appropriate tumor cell line panel yielded 17 compounds with improved potency and cell line selectivity. BLS200 was chosen as lead compound for further development.
