Background: Frizzled-8 (FZD8) receptor is a therapeutic target for cancer treatment and recent research has shown that carbamazepine (CBZ) can inhibit this receptor. Objective: In this work, it has been tried to optimize CBZ to enhance its binding capacity to the N6W binding site of FZD8 by using structure-based drug design methods. Methods: CBZ and its 83 derivatives were docked to the N6W binding site of FZD8. Results: Docking results show that two compounds 79 and 82 have the smallest binding energies and are fitted to the N6W binding site. Compounds C79 and C82 have been synthesized by replacing a hydrogen atom of the seven-membered ring in CBZ with benzoate and nicotinate groups, respectively. In addition, docking results show that a trifluoromethyl on one of the phenyl rings is favorable for improving the FZD8 inhibition activity of the molecule. Conclusion: Both molecules C79 and C82 were subjected to molecular dynamics (MD) simulation. MD results show that FZD8-C82 complex is stable and this compound binds to the N6W binding site more strongly than compounds C79 and CBZ.
