Kinase proteins participate in various signaling pathways that affect the regulation of cellular
processes and are involved in numerous diseases, making them therapeutic targets.
Understanding the function and structure of these proteins and their interactions with
inhibitors can help in the design of new drugs.
In this study, bioinformatic tools are used to investigate the interaction between the kinase
proteins Abl and Src and their ancestral proteins with Imatinib, a kinase inhibitor used to
treat chronic myeloid leukemia. The accuracy of these tools is analysed for molecular
docking calculations (SwissDock) and for predicting 3D protein structures, such as SwissModel and AlphaFold3.
The results of the molecular docking calculations and the comparison of Imatinib binding
modes with its binding in crystallographic structures (PDBs) have determined that
SwissDock is an accurate program for representing interactions between kinase proteins
and Imatinib in Abl, Src, and common ancestor (AS) proteins.
The reconstruction of unresolved structural elements in the studied PDBs through homology
models has helped understand the key role of the orientation of the DFG motif (DFG-out or
DFG-in) and the activation loop in the interactions with Imatinib in these kinase proteins.
For the ancestral proteins A1, A2, and S1, whose structures are unknown, a complete
reconstruction was performed with the Swiss-Model server using PDB 4CSV (DFG-out) and
PDB 4UEU (DFG-in) as templates. None of the predictions obtained a correct binding mode
for Imatinib in the molecular docking calculations. Finally, the structures of Src, AS, A1, A2,
and S1 proteins were also reconstructed with the AlphaFold3 artificial intelligence server.
None of the proposed predictions achieved better results in the molecular docking
calculations with Imatinib compared to crystallographic structures due to poor
preorganization of the DFG motif.
In summary, it is currently necessary to have crystallographic structures to perform accurate
molecular docking calculations in kinase proteins. Expanding the range of DFG
conformations in predictions or being able to add the ligand during structure prediction could
make AlphaFold3 a very useful tool in molecular structure prediction
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