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Under ONIOM Layers: Analysis of BCR-ABL Enzyme Inhibitors Through Bond-Critical Points and Natural Orbitals
Kelvyn M L Rocha1, Érica C M Nascimento2, João B L Martins1,2
1Department of Pharmacy, Faculty of Health Sciences, University of Brasilia, Brasilia 70910-900, DF, Brazil.
Abstract:
Considering the relevance of hydrogen bonds and other intermolecular interactions in regulating the activity of the tyrosine kinase class of enzymes, an in-depth electronic structure study of these forces in the context of the BCR-ABL protein was performed through full optimizations using the ONIOM method. Rebastinib and ponatinib were docked to the target enzyme using AutoDock Vina to provide starting-point geometries, which were then optimized through ONIOM calculations. This study evaluated Frontier Molecular Orbitals (FMOs) and Bond-Critical Points (BCPs) located in the sites of interactions formed with accessible residues, such as Glu286, Met318, and Asp381. Ponatinib's ONIOM-optimized structure was shown to not only form and preserve prominent interactions, which were shown to be significantly stronger than those formed by rebastinib, but also to be associated with a significant increase in the HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap, indicating its potential to hinder catalytic activity by providing higher chemical stability when compared to rebastinib.
Insights
Ponatinib demonstrates stronger interactions and higher chemical stability than rebastinib in BCR-ABL tyrosine kinase inhibition. This suggests ponatinib may be more effective at hindering enzyme activity due to its electronic structure.
Area of Science:
- Biochemistry
- Computational Chemistry
- Structural Biology
Background:
- Tyrosine kinases, like BCR-ABL, are crucial drug targets.
- Intermolecular interactions, including hydrogen bonds, regulate enzyme activity.
- Understanding these interactions is key for drug design.
Purpose of the Study:
- To investigate the electronic structure of intermolecular interactions between BCR-ABL and inhibitors.
- To compare the binding of rebastinib and ponatinib at a molecular level.
- To elucidate the role of electronic properties in kinase inhibition.
Main Methods:
- Molecular docking using AutoDock Vina.
- Quantum chemical calculations using the ONIOM method for full geometry optimization.
- Analysis of Frontier Molecular Orbitals (FMOs) and Bond-Critical Points (BCPs).
Main Results:
- Ponatinib formed stronger and more stable interactions with BCR-ABL residues (Glu286, Met318, Asp381) compared to rebastinib.
- Ponatinib exhibited a significant increase in the Highest Occupied Molecular Orbital (HOMO)-Lowest Unoccupied Molecular Orbital (LUMO) gap.
- This increased HOMO-LUMO gap suggests enhanced chemical stability for ponatinib.
Conclusions:
- Ponatinib's superior binding interactions and increased electronic stability contribute to its potential for effective BCR-ABL inhibition.
- The study provides insights into the molecular mechanisms underlying differential drug efficacy.
- Computational methods like ONIOM are valuable for predicting drug performance based on electronic structure.
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