Targeting human thymidylate synthase: Ensemble-based virtual screening for drug repositioning and the role of water

A drug repositioning computational approach was carried to search inhibitors for human thymidylate synthase. An ensemble-based virtual screening of FDA-approved drugs showed the drugs Imatinib, Lumacaftor and Naldemedine to be likely candidates for repurposing. The role of water in the drug-receptor interactions was revealed by the application of an extended AutoDock scoring function that included the water forcefield. The binding affinity scores when hydrated ligands were docked were improved in the drugs considered. Further binding free energy calculations based on the Molecular Mechanics Poisson-Boltzmann Surface Area method revealed that Imatinib, Lumacaftor and Naldemedine scored -130.7 ± 28.1, -210.6 ± 29.9 and -238.0 ± 25.4 kJ/mol, respectively, showing good binding affinity for the candidates considered. Overall, the analysis of the molecular dynamics trajectory of the receptor-drug complexes revealed stable structures for Imatinib, Lumacaftor and Naldemedine, for the entire simulation time.