Journal
MOLECULAR DIVERSITY
Volume 27, Issue 5, Pages 2257-2271Publisher
SPRINGER
DOI: 10.1007/s11030-022-10554-x
Keywords
Epigenetic therapy; Ubiquitination; FBXW8; Inhibitors; Virtual screening; Pharmacophore modeling
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This study developed an integrated approach to screen FBXW8 inhibitors and identified three compounds with potential as therapeutic candidates for CRL7-related cancers.
FBXW8 plays an irreplaceable role in the substrate recognition of ubiquitin-dependent proteolysis, which further regulates cell cycle progression and signal transduction. However, the abnormal expression of FBXW8 triggers malignancy, inflammation, and autophagy irregulation. FBXW8 is considered as an effective therapeutic target for Cullin-RING ligase 7 (CRL7)-related cancers. Still, the lack of selective inhibitors hinders further therapeutic development and limits the exploration of its biological mechanism. This study constructed an integrated protocol that combines pharmacophore modeling, structure-based virtual screening, and Molecular Dynamic Simulation. It was then used as a screening query to identify hit compounds targeted at the substrate recognition site of FBXW8 from a large-scale compound database including 120 million compounds. Then, ten lead compounds were retrieved by using molecular docking analysis and ADMET prediction. Finally, MD simulations were performed to validate the binding stability of selected drug candidates. The result indicated that three newly obtained compounds, namely ZINC96179876, ZINC72174069, and ZINC97730272, might be potent FBXW8 inhibitors against CRL7-related cancers such as endometrial cancer. [GRAPHICS] .
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