Drug Target Deconvolution Archives - Biognosys

This joint webinar with ETH Zurich features Prof. Dr. Paola Picotti, scientific advisor of Biognosys and inventor of the LiP-MS technology. In the first part of the webinar, Prof. Picotti provides an overview on the development of the LiP-MS workflow in her laboratory starting from the concept of detecting protein structural alterations in complex matrices to its various applications in addressing biological questions such as metabolite-protein interactions, protein aggregation and thermal stability. In the second part of this webinar, Biognosys’ senior scientist Dr. Nigel Beaton focuses on establishing a machine learning-based LiP-MS workflow for the deconvolution of small molecule drug targets in an unbiased manner.

LiP-MS is a recent addition to the target deconvolution toolbox which can effectively identify protein drug targets and characterize the binding properties in complex proteomes independent of the compound’s MoA and without compound modification or labeling.

Target identification in a physiologically relevant context is a critical step in both target-based and phenotypic drug discovery. Limited proteolysis coupled with mass spectrometry (LiP-MS) has recently emerged as a robust strategy for deconvoluting the protein targets of small molecules and peptides directly in complex cell lysates, without requiring chemical derivatization of compounds or genetic engineering of cell models. In LiP-MS, a broadly active protease is applied under controlled conditions, generating peptide fingerprints that reflect drug-induced structural perturbations or steric protection at the protein level. When combined with quantitative mass spectrometry, this approach can interrogate more than 250,000 peptides, corresponding to up to ~9,000 proteins in the proteome.

In addition to global target identification, we developed a high-resolution LiP (HR-LiP) workflow for targeted characterization of small molecule–protein interactions directly in cell lysates from overexpression systems. This approach eliminates the need for protein purification, avoiding artifacts such as truncation or misfolding.

Contact