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

许多与治疗相关的蛋白质，包括较大受体靶点的结构域，缺乏明确的三维形状。这使得利用现有的基于结构的方法（如蛋白质晶体学）寻找这些靶点的新线索成为一项特别的挑战。尽管如此，许多这样的前蛋白仍然有很大的兴趣，因此，寻找这些靶点的新方法具有重要的当代意义。通过利用斯特拉斯克莱德在开发理解反应性弹头方面开发的能力，如腈亚胺和相关物种，该项目旨在通过天然质谱法和其他相关生物物理技术，使用反应性片段筛选方法，为雄激素受体（一种内在无序的蛋白质结构域）的氨基末端区域找到新的配体。在相关的基于细胞的分析中验证命中的化合物将提供具有注释生物活性的合格先导物，从而验证所提出的方法。该项目有可能产生大量的绑定和功能数据，可以使用AI/ML技术进一步利用这些数据来找到最佳的线索。

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.