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Innovative Medicines & Omics Modeling Aurora-B kinase inhibitors

A detailed SAR analysis was performed to evaluate how sourced from the Maybridge and NCI databases. These
specific molecular features influence the binding affinity lead compounds showed interactions with the Aurora-B
and inhibitory potential of the lead compounds. Effective binding pocket, underscoring their potential for further
kinase inhibitors rely on key pharmacophoric features exploration. Specifically, we found that LYS 106, ALA
facilitating interactions with the active site of the Aurora-B 157, GLU 161, and PHE 219 play pivotal roles in ligand
kinase protein. These features include hydrogen bond binding, highlighting these residues as key targets for
donors and acceptors, hydrophobic regions, aromatic future Aurora-B inhibitor development.
rings, charged functional groups, and other functional
moieties – such as benzimidazole, benzothiazole, Acknowledgments
and benzodioxole. The molecular docking and MD None.
simulations provided insights into these interactions,
revealing that hydrogen bond formation plays a crucial Funding
role in stabilizing the protein-ligand complex. The lead None.
compounds demonstrated varying degrees of hydrogen
bonding with key amino acid residues, such as ALA 157, Conflict of interest
LYS 106, and PHE 219, reinforcing their role in kinase
inhibition. Furthermore, π-π stacking and hydrophobic The authors declare that they have no competing interests.
interactions observed in multiple lead compounds Author contributions
suggest that aromatic moieties are essential for improving
binding affinity. Electrostatic interactions, particularly Conceptualization: Athavan Alias Anand Selvam, Kabilan
those involving nitrogen and sulfur-containing functional Senthamaraikannan
groups, contributed significantly to the stability of some Formal analysis: Athavan Alias Anand Selvam, Sunil
lead compounds, mirroring similar interaction patterns Kumar Bandral
observed in known Aurora-B inhibitors. Water bridge Investigation: Kabilan Senthamaraikannan
interactions further supported the stabilization of the Methodology: Athavan Alias Anand Selvam
complexes, emphasizing the role of solvent-mediated Visualization: Athavan Alias Anand Selvam
interactions in ligand binding. MD simulations confirmed Writing – original draft: Athavan Alias Anand, Parasuraman
the dynamic behavior of the lead compounds, with RMSD Pavadai
plots indicating stable conformations within the binding Writing – review & editing: Athavan Alias Anand Selvam,
pocket. Collectively, the structural comparison and SAR Kabilan Senthamaraikannan
analysis suggest that the identified lead compounds exhibit Ethics approval and consent to participate
key pharmacophoric features essential for Aurora-B
kinase inhibition. Their resemblance to known inhibitors, Not applicable.
both in core scaffold architecture and functional group
distribution, strongly supports their potential as promising Consent for publication
drug candidates. Not applicable.

4. Conclusion Availability of data
Our findings suggest that the AADRR pharmacophore Data are available from the corresponding author on
model, docking studies, and MD simulations provide reasonable request.
valuable structural insights for Aurora-B kinase inhibition.
Notably, previous studies identified interactions between Further disclosure
specific residues (LEU 83, PHE 88, VAL 91, ALA 157, The paper has been deposited in a preprint server (https://
and GLU 155) within the Aurora-B binding pocket, doi.org/10.1101/2024.07.29.605534)
leading to the development of a pharmacophoric model
with seven distinct features, including two hydrophobic References
elements, one donor, one acceptor, and three exclusion
volumes. However, our study introduced a five-feature 1. Al-Rawi DH, Lettera E, Li J, DiBona M, Bakhoum SF.
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superior predictive parameters based on PLS analysis. This
approach led to the identification of five promising lead doi: 10.1038/s41571-024-00923-w
compounds from a screening pool of 320,000 compounds 2. Bischoff JR, Anderson L, Zhu Y, et al. A homologue of

Volume 2 Issue 2 (2025) 110 doi: 10.36922/imo.6547