Structure-based design of plant-based dual inhibitors targeting AURKA1 and HDAC2 as potential anticancer agents

Cancer is a complex metabolic disorder marked by uncontrolled cell proliferation and resistance to conventional therapies, often due to non-selectivity and acquired drug resistance. Aurora kinase A (AURKA) plays a key role in mitosis, while histone deacetylase 2 (HDAC2) regulates gene expression via epigenetic mechanisms. Dual inhibition of these targets may disrupt complementary oncogenic pathways, offering a strategy to overcome resistance. The structure-based computational methods were implemented to identify the most potent plant-based dual inhibitors for simultaneous targeting AURKA and HDAC2 receptors. A phytochemical-based ligand library comprising over 70 plant-derived ligands selected based on the structural diversity of the concerned ligands and plants with reported anticancer activity was prepared and subjected to molecular docking against AURKA and HDAC2. Top hits were further evaluated using molecular dynamics (MD) simulations to assess their binding stability and interaction profiles against the concerned targets. Among the screened compounds, nummularogenin, a triterpenoid, emerged as the most promising dual inhibitor, demonstrating strong binding affinities with a docking score of −9.70 kcal/mol for AURKA and −7.79 kcal/mol for HDAC2. Molecular dynamics analysis revealed stable interactions with both AURKA and HDAC2, indicated by root mean square deviation (RMSD) values ranging between 6.5 and 12.0 Å for AURKA and 0.8–1.4 Å for HDAC2. These interactions were stabilized through interaction with key catalytic pocket residues, including Val147, Ala160, and Asp274 in AURKA and His33, Arg275, and Tyr308 in HDAC2 receptors, respectively. Nummularogenin was revealed as a promising plant-based dual-targeting agent interrupting both the vital processes of the cell division process and epigenetic regulation of the cancerous cells at the transcriptomic level, which further needs to be validated through preclinical and clinical investigations for its anticancer potential.