Novel hybrid virtual screening protocol based on pharmacophore and molecular docking for discovery of GSK‐3β inhibitors

Abstract

GSK‐3β is a member of the GSKs subfamily and plays a major role in the regulation of transcriptional elongation, which has attracted widespread attention as a therapeutic target for AD. In this study, by combining pharmacophore‐based virtual screening and kinase inhibition assays, we have successfully identified four small molecules that inhibit GSK‐3β activity at micromolar potency. These hit compounds showed drug‐like properties according to Lipinski's rule of five and ADMET. An inter‐complex interaction study showed that all hit compounds adapted well to the ATP pocket of the GSK‐3β protein. Among them, hits 2 and 4 displayed considerable inhibitory activities with IC50 value of 0.74 ± 0.04 μM and 2.32 ± 0.84 μM respectively. Overall, the discovered GSK‐3β inhibitors act as new chemical leads to develop improved inhibitors that block the interaction of GSK‐3β, and the hybrid virtual screening strategy designed in this study provides an important reference for design and synthesis novel selective GSK‐3β inhibitors.

Elucidation of the mechanism of action of ailanthone in the treatment of colorectal cancer: integration of network pharmacology, bioinformatics analysis and experimental validation

“…This study evaluated the drug-like properties of AIL using the SwissADME database by applying Lipinski’s rule, a guideline for drug design and screening ( Liu et al, 2023 ). The results revealed that the ADME parameters of AIL (MW = 376.40 Da; Hdon = 3; Hacc = 7; AlogP = −0.32; RBN = 0) meet Lipinski’s rule parameters, suggesting satisfactory medicinal properties.…”