Ensemble-based virtual screening in discovering potent inhibitors targeting Von Hippel-Lindau (VHL) E3 ubiquitin ligase

Abstract

BackgroundThe Von Hippel-Lindau (VHL) E3 ubiquitin ligase, which mediates its substrate hypoxia-inducible factor 1α (HIF-1α) for ubiquitination and subsequent degradation, is an attractive drug target in various diseases, such as anemia, inflammation, neurodegeneration and cancer. Proteolysis targeting chimeras (PROTACs) containing a VHL ligand that can hijack the E3 ligase activity to degrade the target protein has also been studied in academic and in industry areas recently. MethodsHerein, by developing and optimizing the Bayesian Model, we report ensemble-based virtual screening as an effective strategy to discover potential VHL inhibitors from Specs database. ResultsThe virtual screening protocol was developed, ten representative molecules were obtained and five compounds were selected for subsequent binding mode analysis to be potent VHL inhibitors.