Studies of N9-arenthenyl purines as novel DFG-in and DFG-out dual Src/Abl inhibitors using 3D-QSAR, docking and molecular dynamics simulations

Recently, the development of Src/Abl (c-Src/Bcr–Abl tyrosine kinases) dual inhibitors has attracted considerable attention from the research community for treatment of malignancies. In order to explore the different structural features impacting the Src and Abl inhibitory activities of N9-arenethenyl purines and to investigate the molecular mechanisms of ligand–receptor interactions, a molecular modeling study combining the three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations was performed. The obtained CoMFA (comparative molecular field analysis) models exhibited satisfactory internal and external predictability. The plots of the CoMFA fields could be used to investigate the structural differences between DFG-in (targeting the active enzyme conformation) and DFG-out (targeting the inactive enzyme conformation) inhibitors. The key amino acid residues were identified by docking studies, and the detailed binding modes of the compounds with different activities were determined by MD simulations. The binding free energies gave a good correlation with the experimental determined activities. In an energetic analysis, the MM-PBSA (molecular mechanics Poisson–Boltzmann surface) energy decomposition revealed that the van der Waals interactions were the major driving force for the binding of the DFG-in and DFG-out compounds to Src and Abl, especially the hydrophobic interactions between ligands and residues Ala403/380, Asp404/381, and Phe405/382 in DFG-out Src and Abl complexes. They also help to stabilize the DFG-out conformations. These results can offer useful references for designing novel potential DFG-in and DFG-out dual Src/Abl inhibitors.