# Under ONIOM Layers: Analysis of BCR-ABL Enzyme Inhibitors Through Bond-Critical Points and Natural Orbitals

## TL;DR

This study compares how rebastinib and ponatinib interact with the BCR-ABL enzyme using advanced computational methods to assess their effectiveness.

## Contribution

The paper introduces a detailed electronic structure analysis of BCR-ABL enzyme inhibitors using ONIOM and BCPs.

## Key findings

- Ponatinib forms stronger interactions with key residues like Glu286, Met318, and Asp381 compared to rebastinib.
- Ponatinib shows a larger HOMO-LUMO gap, suggesting greater chemical stability and potential to inhibit catalytic activity.
- ONIOM calculations revealed significant differences in the electronic properties of the two inhibitors.

## 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.