Evaluation of novel Akt1 inhibitors as anticancer agents using virtual co-crystallized pharmacophore generation.
The pharmacophoric features of the virtual co-crystallized protein of 17 Akt1 proteins were downloaded from the protein data bank, and explored to end up with 132 generated pharmacophores that had been evaluated using the decoy list composed of 1724 compounds. The areas under the curve of the Receiver-Operating Characteristic (ROC-AUC) were sorted, and the highest ranked pharmacophore 3MV5_2_01 was selected to be used as a searching tool in the National Cancer Institute (NCI) database. The captured hits were mapped based on successful hypotheses and the best fitted compounds were selected. The inhibition of Akt1 was measured and expressed as a percentage of inhibition. 24 out of the 40 compounds showed inhibition of Akt1, out of which 13 compounds showed more than 50% inhibition. Compound 1 showed 93.3% inhibition at 100 μM concentration. To confirm the inhibition of Akt1 phosphorylation, MCF10A cell line was co-treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and 100 μM of each of the most potent 13 Akt inhibitors (1-13). It was found that compounds 1 exert 91.6% inhibition of Akt1 phosphorylation in MCF10A cell line.
Faculty of Pharmacy, Zarqa University, P.O.Box 132222, Zarqa, 13132, Jordan. Electronic address: a.mahmoud@zu.edu.jo.
Mahmoud A
MA
Al-Sha'er
Faculty of Pharmaceutical Sciences, The Hashemite University, P.O. Box 330127 Zarqa, 13115 Jordan.
Iman
I
Mansi
Faculty of Pharmacy, Zarqa University, P.O.Box 132222, Zarqa, 13132, Jordan.
Inas
I
Almazari
Faculty of Pharmacy, Zarqa University, P.O.Box 132222, Zarqa, 13132, Jordan.
Nancy
N
Hakooz
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000737:chemistry*; D012372:ROC Curve
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
Akt1; Cancer; Co-crystallized structure; Cox-2; Docking; MCF10A; Pharmacophore; Roc analysis