Objectives: This study aims to assess the drug-likeness and binding of nucleobase-substituted ponatinib analogues towards wild-type and T315I mutant BCR-ABL tyrosine kinases. Methodology: A total of 415 ponatinib analogues, encompassing single and combinatorial modifications on five parts of the drug were generated, profiled in SwissADME, and subjected to molecular docking using AutoDock4. Complexes formed by the top analogues then underwent a 100-ns molecular dynamics simulation with GROMACS. Results: Analogues featuring the replacement of the imidazo[1,2b]pyridazine with adenine and cytosine exhibited promising binding free energies, attributed to the presence of primary amines that facilitate crucial hydrogen bond interactions in the hinge region. RMSD, RMSF, and atomic distance analyses of the MD trajectories revealed that the six top analogues formed stable complexes in their inactive DFG-out conformations. Changes in the MMPBSA and MMGBSA-calculated free energies were mainly driven by changes in hydrogen bonds. Furthermore, drug-likeness predictions supported the formulation of most analogues for oral administration. Conclusion Among the top analogues, VP10004 and VP81014 exhibited the most favorable binding free energies and interactions with the target models, while VP10312 was identified as the most feasible candidate for synthesis.
Hydrogen Bonding ; Molecular Dynamics Simulation ; Molecular Docking Simulation