Identification of New Ligands for Disordered Protein Domains Through Reactive Fragment Screening

Many proteins of therapeutic relevance, including domains of larger receptor targets, lack a well-defined three dimensional shape. This makes finding new leads for these targets a particular challenge using established structure-based methods such as protein crystallography. Despite this, many such preoteins remain of significant interest, therefore, new approaches to lead finding for such targets are of significant contemporary importance. Through exploiting capability developed at Strathclyde in developing understanding reactive warheads, such as nitrile imine and related species, this project aims to find new ligands for the amino terminal domain of the Androgen Receptor (an intrinsically disordered protein domain) using a reactive fragment screening approach via native mass spectrometry and other related biophysical techniques. Validation of the hit compounds in relevant cell-based assays will furnish qualified leads with annotated biological activity, thus validating the proposed approach. This project has the potential to generate a large volume of binding and functional data which can be further leveraged using AI/ML techniques to find the optimum lead.