Interaction mechanism of novel fluorescent antifolates targeted with folate receptors α and β via molecular docking and molecular dynamic simulations

Eight novel fluorescent antifolates were designed and docked with folate receptors FRα and FRβ. The structures of the complexes were further calculated by molecular dynamic (MD) simulations. The binding energies were calculated by molecular docking and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) studies. The binding energy differences between FRα and FRβ (|E_bα|-|E_bβ|) values for compounds 3 and 8 were 1.3 and 1.1 kcal/mol calculated by molecular docking, and 13.9 and 10.4 kcal/mol by MM-PBSA simulation, respectively. The results indicated that compounds 3 and 8 may be the best candidates for targeted drug delivery to FRα. The binding structures, interaction residues, negatively charged pocket volume, and surface area were analyzed for all the complexes. We further calculated the root mean square displacement and secondary structural elements of the bound complexes using molecular dynamics simulations. The purpose of this study is to design novel antifolates targeted to FRα and FRβ, and to further distinguish between cancer cells and inflammation.