Dual-Target Anticancer Drug Candidates: Rational Design and Simulation Studies

This study aims to design some dual-target anticancer candidates, capable to act as an alkylating agent as well as a thymidylate synthase (TS) inhibitor. The designed scaffold is a combination of nucleobase, amino acid and aziridine structures. The candidates are docked into TS and three DNA double strand structures and evaluated based on their binding interaction energies and ligand efficiencies, compared to several reference drugs. The ADME properties of the alkylating agents are also predicted. The designed ligands exhibit improved interaction energies and lower ligand efficiencies with respect to the reference drugs. Among the ligands, L4 is the best DNA binding agent and L2, L5 and L6 are the best TS inhibitors. In addition, the thioTEPA based Ser and Met analogues are the strongest and poorest alkylating agents, respectively. Further, molecular dynamics simulations on the best ligand-target complexes, i.e. L4-4AWL and L6-TS systems, provide evidences for the potential L6 and L4 anti-proliferation activities.