Insights into subtype selectivity of aurora kinase ligands from molecular dynamics simulation

Abstract

Aurora kinases are phosphotransferase enzymes that play essential roles in cell division. There are three members of Aurora kinases in mammalian cells: Aurora A, Aurora B and Aurora C. The overexpression of Aurora kinases in diverse cancer cells make them promising targets in cancer therapy. Aurora kinases show highly conserved homology, having four different residues in the active site: Leu215, Thr217, Val218, and Arg220 in Aurora A (Arg159, Glu161, Leu162 and Lys164 in Aurora B). Therefore, understanding Aurora kinase inhibitor selectivity remains a top priority for kinase inhibitor design. The utilization of molecular dynamics simulations for kinase selectivity studies could provide insights into ligand-protein interactions, including key residues, predominant free energy contributions, and interaction types, facilitating the design of subtype-selective inhibitors. To elucidate the subtype selectivity mechanism of Aurora kinase A and B, molecular docking was employed to construct complex structures. Subsequent MD simulations were conducted for complexes of Aurora A and B with selective inhibitors LY3295668, MK-5108, and Alisertib, as well as Aurora B selective inhibitor GSK-1070916 and pan-inhibitor Danusertib. The analysis included RMSD, average structure determination, MM/PBSA-derived binding free energy, and decomposition analysis, elucidating favorable or unfavorable residue contributions within the active site. For Aurora A selective inhibitors (LY3295668, MK-5108, and Alisertib), the residue Thr217 and Arg220/137 emerged as crucial for selectivity, with the carboxylate group being the predominant functional group contributing significantly to binding free energy in these compounds. Conversely, GSK-1070916's selectivity for Aurora B was attributed to Arg159 and Asp218, with its tertiary amine with methyl group being key functional groups. These findings on subtype selectivity mechanisms hold promise for the development of highly selective Aurora kinase inhibitors, offering a less toxic anti-cancer strategy.