Type and size effect of functional groups on the novel antifolate target recognition folate receptors α and β: Docking, molecular dynamics and MM/PBSA study.

A series of novel antifolates (32 compounds) were used to study the interactions with folate receptors α and β. The compounds had different sizes of methyl (-CH), carboxyl (-COOH), hydroxyl (-OH), and amino groups (-NH). The binding properties of the complexes were studied by molecular docking, molecular dynamic (MD) simulations, and MM/PBSA free energy calculations. The docked binding energies and modes were analyzed to identify compounds with good recognition of FRα from FRβ. The stable conformers, root mean square displacement, root mean square fluctuation free binding energy, and contribution of residues to the binding energy of the complexes were further analyzed to illustrate the interactions between the novel compounds and folate receptors. The data show that introducing long functional groups in folate will increase the binding affinity with FRα but will decrease the binding affinity with FRβ. The results provide a strategy for the design of novel antifolates targeted to FRα.