Abstract
In silico docking studies of 50 selected compounds from Millettia dielsiana Harms ex Diels (family Leguminosae) were docked into the binding pocket of the PI3K/mTOR protein. In there, compounds trans-3-O-p-hydroxycinnamoyl ursolic acid (1) and 5,7,4'-trihydroxyisoflavone 7-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (2) are predicted to be very promising inhibitors against PI3K/mTOR. They direct their cytotoxic activity against Hepatocellular carcinoma with binding affinity (BA) values, the pulling work spent to the co-crystallized ligand from the binding site of PI3K/mTOR (W and F(max)), and the non-equilibrium binding free energy (∆G(neq)(Jar)) as BA values = -9.237 and -9.083 kcal/mol, W = 83.5 ± 10.6 kcal/mol with F(max) = 336.2 ± 45.3 pN and 126.6 ± 21.7 kcal/mol with F(max) = 430.3 ± 84.0 pN, and ∆G(neq)(Jar) = -69.86074 and -101.2317 kcal/mol, respectively. In molecular dynamic simulation, the RMSD value of the PI3K/mTOR complex with compounds (1 and 2) was in the range of 0.3 nm to the end of the simulation. Therefore, the compounds (1 and 2) are predicted to be very promising inhibitors against PI3K/mTOR. The crude extract, ethyl acetate fraction and compounds (1 and 2) from Millettia dielsiana exhibited moderate to potent in vitro cytotoxicity on Hepatocellular carcinoma cell line with IC(50) values of 81.2 µg/mL, 60.4 µg/mL, 23.1 μM, and 16.3 μM, respectively, and showed relatively potent to potent in vitro antioxidant activity on mouse hepatocytes with ED(50) values of 24.4 µg/mL, 19.3 µg/mL, 30.7 μM, and 20.5 μM, respectively. In conclusion, Millettia dielsiana and compounds (1 and 2) are predicted to have very promising cytotoxic activity against Hepatocellular carcinoma and have a hepatoprotective effect.