DUGi

Aplicació i validació d’eines bioinformàtiques per a la predicció d’interaccions proteïna-inhibidor en proteïnes quinasa

http://dugi.udg.edu/item/http:@@@@hdl.handle.net@@10256@@26328

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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