Exploiting Avidity Effects for the Discovery of Low Affinity Protein-Binding Fragments.

ABSTRACT: Fragment-based drug discovery (FBDD) is a powerful approach to the development of pharmaceuticals and probe molecules and there is broad interest in the development of new platforms for their discovery. Here, we introduce a workflow in which low molecular weight organic molecules displayed on the surface of TentaGel beads are exposed to a multimeric, fluorescently labeled target protein. Using tetrameric or dimeric protein targets, we show that beads that display even weak ligands (K_Ds in the high μM to low mM range) stably capture the protein due to avidity effects, thus allowing a simple "pull-down" protocol to be employed for fragment discovery. We also demonstrate that the platform is capable of supporting a "fragment growth" screen, which is a typical strategy to adv

SUBMITTER: Jayalath IM 

PROVIDER: S-EPMC12598851 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature