Dynamic Structure-based Pharmacophore Models for Virtual Screening of Small Molecule Libraries Targeting the YB-1

Abstract

AbstractIn drug discovery, ligand-based techniques offer rapid screening, whereas structure-based approaches provide deeper insights but are time-consuming. Hybrid methods like structure-based pharmacophore models combine advantages for accurate screening of large ligand libraries. However, there are substantial limits to build structure-based pharmacophore models. Static models relying on a single co-crystallized structure or docking pose often fall short in capturing the dynamic nature of binding interactions. In this study, we present dynamic structure-based pharmacophore models, aimed at better representing physiological conditions and addressing these challenges. The urgent need for improved cancer treatment has led to the search for new chemotherapeutic strategies. Y box binding protein 1 (YB-1) is a multifunctional protein associated with tumor progression and treatment resistance in various cancers. For the first time in the literature, our study utilizes a known small molecule YB-1 inhibitor (SU056) bound to the active regions of the RNA-binding sites to develop dynamic structure-based pharmacophores. These models were then used in the screening of large ligand libraries.