A combined approach based on 3D pharmacophore and docking for identification of new aurora A kinase inhibitors

Aurora kinase A is involved in multiple mitotic events in cell cycle and has been identified as a major regulator of centrosome function in mitosis. Aurora A has been found to be over-expressed in many tumor types including breast, lung, colon, ovarian, pancreatic and glial cells. Thus, inhibition of aurora A can be a potential target in oncology. A five-point pharmacophore was generated using PHASE for a set of aurora A inhibitors reported in literature. The generated pharmacophore yielded statistically significant 3D-QSAR model, with a correlation coefficient r 2 of 0.936 and q 2 of 0.703. The pharmacophore indicated that presence of two aromatic ring features (R), two acceptor features (A) and one donor feature (D) is necessary for potent inhibitory activity. The database screening was done initially by use of pharmacophore followed by an interaction-based selection using docking. Twelve hits with satisfactory pharmacokinetic properties have been identified.