s Identification of Novel GSK1070916 Analogs as Potential Aurora B Inhibitors: Insights from Molecular Dynamics and MM/GBSA Based Rescoring

The discovery of promising targets for anticancer drug development has emerged with many potential enzymes. Among these, the aurora family of kinases has become a very lucrative target with some potential inhibitors in its arsenal. Recent findings show that targeting aurora B itself is sufficient to exhibit anticancer activity. When compared with other anticancer targets, aurora B has a very limited number of specific inhibitors. Recently GSK1070916 and reversine were discovered as promising new aurora B inhibitors. Amongst these GSK1070916 emerged as the most potent molecule targeting aurora B. Taking the scaffold of GSK1070916 as a reference, new molecules were designed by isosteric/ bioisosteric and fragment based modifications. Furthermore, an accurate cross-platform docking, MM/GBSA based rescoring, molecular dynamics simulation were carried out to compare the binding conformation and affinities of the designed molecules with the references. Top two designed molecules showed better docking score and a better binding free energy profile as compared to reversine and GSK1070916 with the best ligand retaining conserved hydrogen bond and salt bridge interactions with Ala173, Ala233 and Lys122. The binding mode of top two designed ligands is relatively similar to that of reversine and GSK1070916. Molecular dynamics simulations proved that the identified hits are rather stable in the enzyme active site pocket, which further confirms the potential of the designed ligands as a specific target for aurora B. We believe that findings of this study will provide medicinal chemists with potential markers towards the design of potent anticancer drug design targeting aurora B and a broad range of aurora kinases.