Pharmacophore identification, virtual screening and biological evaluation of prenylated flavonoids derivatives as PKB/Akt1 inhibitors

A total of 24 well-defined PKB/Akt1 inhibitors were used to generate pharmacophore models applying Catalyst/HypoGen program. The best ranked model (Hypo_1) was then validated by cost analysis, prediction capability, Cat-Scramble and receiver operating characteristic (ROC) studies. Then, pharmacophore-based virtual screening combined with docking study was performed to search an in-house compound database. Nine preferable hits 75–80, HTS-02143, BTB-14740 and HTS-08006 were prepared and biologically evaluated. Several compounds were identified as good PKB/Akt1 inhibitors, suggesting that Hypo_1 would be reliable and useful in virtual screening. Flow cytometric and western blotting analysis on compounds 79 and 80 further demonstrated that the inhibition of phosphorylation of PKB/Akt1 and its substrates (such as GSK3β) was responsible for their cytotoxic activities.

Graphical abstractPharmacophore-based virtual screening combined with docking studies was performed to search an in-house database. A total of nine preferable hits were selected and biologically assayed. Several compounds were identified as good PKB/Akt1 inhibitors.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We established a pharmacophore model of PKB/Akt1 inhibitors using HypoGen program. ► We performed pharmacophore-based virtual screening combined with docking studies. ► Several novel PKB/Akt1 inhibitors were identified and biological evaluated. ► The benzopyran skeleton was firstly found in PKB/Akt1 inhibitors.