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

Abstract

In 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.

Inhibition of protein translational machinery in triple-negative breast cancer as a promising therapeutic strategy

“…In a structure-based pharmacophore model, SU056 demonstrates binding with YB-1 through π-π stacking or π-cation interactions, mimicking the protein-RNA interactions as the CSD. 47 Our findings show that SU056 inhibits YB-1 binding to nascent mRNAs via its RNA-binding site and also inhibits the interaction between YB-1 and RPL11, in turn suppressing translation. YB-1 knockdown reversed SU056-mediated translation inhibition, suggesting that this mechanism depends on YB-1.…”

Employing Steered MD simulations for Effective Virtual Screening: Active Pharmacophore Search by Dynamic Corrections to target MKK3-MYC Interactions

“…Using structure-based pharmacophores in combination with all-atom MD simulations is an advanced method known as dynamic pharmacophore modeling 30,31 . With a particular emphasis on identifying the traits that constantly predominate, our method carefully examines the pharmacophoric features that manifest throughout the simulation frames.…”