Assay Development and Screening
Biochemical & Biophysical Assays
In the post-genomic era, abundant functional genomic data is being generated and lists of potential new druggable targets are being analysed across industry and academia. Bioinformatics and literature diligence can take us so far, but there are two key aspects to target selection that are best examined empirically: tractability and ligandability. We have developed a high-throughput fragment screening approach we call Fragment Based Target Screening (FBTS) to examine this.
The FBTS approach has been exemplified at LifeArc in its application to antibacterials. New antibacterial drugs are urgently needed to tackle the emerging crisis of multidrug-resistant infections. 50 potential targets were selected by bioinformatic analysis from a TraDIS dataset of essential genes. Our high-throughput expression and purification platform was used to test the targets for expression. Biophysical techniques were used to QC 38 proteins and match them with a control ligand. Proteins were screened against a library of 1280 fragments on a Biacore 8K, then hits confirmed in dose-response experiments. Automated data-processing and machine learning were applied to assign a ligandability score to each target & prioritise hit fragments for progression. This was combined with additional essentiality data & a progression assessment to compile a priority list of targets to advance into drug discovery projects.
FBTS is accessible; fragment libraries and the equipment needed for protein production and fragment screening are not only in the domain of big pharma, and the cost and effort associated less daunting than that typically associated with other screening options such as HTS or DNA-encoded libraries. In addition, the approach lends itself to take advantage of the wealth of structural data from public databases and structural genomics consortia. Combined with novel functional genomic data, our empirical tractability and ligandability assessment allows high quality targets to be prioritised for prosecution and improved chances of success.