Ensemble-based virtual screening in discovering potent inhibitors targeting Von Hippel-Lindau (VHL) E3 ubiquitin
1School of Chemical Engineering, Sichuan University of Science & Engineering, 180 Xueyuan Street, Huixing Road, Zigong, Sichuan 643000, China.
Background:
The 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.
Methods:
Herein, 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.
Results:
The 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.
