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Innovative Medicines & Omics Modeling Aurora-B kinase inhibitors

Figure 7. The 2D view of protein-ligand interactions after MD simulations for the five lead compounds identified from NCI database as potent Aurora-B
inhibitors
Abbreviations: MD: Molecular dynamics; NCI: National Cancer Institute.

its structural stability. Compound 4 displayed a complex – Hesperadin, VX680, and ZM447439 – revealed crucial
interaction profile, forming hydrogen bonds with ALA 157 pharmacophoric similarities supporting their potential
and GLU 204, π-π stacking interactions with PHE 88, and a as effective inhibitors. Several lead compounds exhibit
crucial water bridge interaction with LYS 106, indicating an conserved core scaffolds and functional groups known
extensive network of stabilizing forces. Compound 5, which to facilitate kinase inhibition, reinforcing their relevance
exhibited the most favorable stability profile, demonstrated as promising candidates for further development.
strong hydrogen bonding interactions with ALA 157, GLU Compounds 1, 2, and 4 contain bicyclic heterocyclic
155, GLU 204, and GLY 84, while LYS 202 contributed to systems such as benzimidazole, benzothiazole, and
additional stabilization through π-cation interactions. benzodioxole, which structurally resemble the indole
A comparative analysis of molecular docking and MD core of Hesperadin. These bicyclic moieties are well-
simulation results revealed a strong correlation between the documented for stabilizing kinase-inhibitor interactions
residues involved in binding interactions. Key residues, such through hydrogen bonding and π – π stacking within
as ALA 157, LYS 106, and PHE 219, identified in docking the ATP-binding pocket. Compound 5 and compound
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studies, were also observed in MD simulations, reinforcing 4 feature quinoline and pyrido-pyrazine frameworks,
the accuracy of docking-based predictions. The comparison respectively, which are analogous to the quinazoline core
of protein-ligand interactions in molecular docking and MD of ZM447439, suggesting similar binding orientations and
simulations is provided in Table 4. Furthermore, statistical inhibitory potential. In addition to core scaffolds, specific
analysis using histograms provided deeper insights into the functional groups within the lead compounds further
frequency and distribution of intermolecular interactions, enhance their potential for kinase inhibition. Sulfur and
including hydrogen bonding, hydrophobic interactions, nitrogen heteroatoms, which play a key role in modulating
ionic interactions, and water bridge formations (Figure 8). electronic properties and molecular interactions, are
The presence of consistent hydrogen bonding interactions present in both Hesperadin and VX680. Notably,
throughout the simulation period underscores their critical compound 2 contains these heteroatoms, enhancing its
role in ligand stability and affinity. ability to form critical hydrogen bonds and coordination
interactions with Aurora-B active site residues. The amide
3.5. Structural comparison and structure-activity functional group, a known pharmacophoric feature
relationship (SAR) analysis associated with enhanced binding affinity and molecular
A comparative structural analysis of the identified lead stability, is present in compound 4, aligning with its
compounds and the established Aurora-B kinase inhibitors presence in all three reference inhibitors. In addition, the

Volume 2 Issue 2 (2025) 108 doi: 10.36922/imo.6547