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.
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Xiaowu
X
Dong
Xinglu
X
Zhou
Hui
H
Jing
Jianzhong
J
Chen
Tao
T
Liu
Bo
B
Yang
Qiaojun
Q
He
Yongzhou
Y
Hu
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D054876:Prenylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt