Molecular docking/dynamics studies of Aurora A kinase inhibitors

The binding modes of a known 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole, quinazoline, pyrimidine and indolinone series of Aurora A kinase inhibitors have been studied using molecular docking and molecular dynamics (MD) simulations. Crystallographic bound compound 8 was precisely predicted by our docking procedure as evident from 0.43 angstrom root mean square (rms) deviations. In addition compound 25 (AZ_68) has been successfully cross-docked within the Aurora A kinase active site, which was pre-organized for inhibitor 8. We found four key sites (A: solvent-exposed front pocket, B: hinge region, C: selectivity pocket and D: solvent-exposed phosphate binding region) of the Aurora A kinase contributing towards the binding of these compounds. We suggest that the small hydrophobic substituents at C-6 position of pyrrolopyrazole nucleus (in compounds 1-8); C-6 and C-7 positions of the quinazoline moiety (in compounds 9-23); C-2 position of the quinazoline and C-4 position of the pyrimidine (in compound 25) could be more effective and selective through increased hydrophobic contacts and selectivity pocket interactions with these modifications of Aurora A kinase inhibitors. Five representative complexes were subjected to 1000 ps of MD simulation to determine the stability of the predicted binding conformations. The low value of the root mean square deviations (ranging from 0.725 to 1.820 angstrom) between the starting complex structure and the energy minimized final average complex structure suggests that the Glide Extra Precision (XP) derived docked complexes are in a state of near equilibrium. The structure-based drug design strategy described in this study will be highly useful for the development of new inhibitors with high potency and selectivity. (C) 2007 Elsevier Inc. All rights reserved.