Some insights into the binding mechanism of Aurora B kinase gained by molecular dynamics simulation.
Aurora B kinase is essential in the process of mitosis, and its overexpression has been reported to be associated with a number of solid tumors. We therefore carried out molecular docking, molecular dynamics, and molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) calculations on several structurally diverse inhibitors (pentacyclic, pyrimidine, quinazoline, and pyrrolopyridine derivatives) and Aurora B kinase to explore the structural and chemical features responsible for the binding recognition mechanism. Molecular simulations reveal that the binding site mainly consists of six binding regions (sites A-F). We have identified that sites B and C are required for optimum binding in Aurora B-inhibitor complexes, sites A and F are needed to improve pharmacokinetic properties, while sites D and E lead to enhanced stability. We verified that hydrogen bonding to the hinge region and hydrophobic contact with the conserved hydrophobic pocket are of critical importance in the systems studied. Specifically, the amino acids Glu171, Phe172, and Ala173 in the hinge region and Leu99, Val107, and Leu223 in the conserved hydrophobic pocket probably account for the high binding affinities of these systems, as shown by hydrogen-bonding analysis and energy decomposition analysis. Hydrophobic contact with Phe172 is also in agreement with experimental data. In addition, the MM-PBSA calculations reveal that the binding of these inhibitors to Aurora B kinase is mainly driven by van der Waals/nonpolar interactions. The findings of this study should help to elucidate the binding pattern of Aurora B inhibitors and aid in the design of novel active ligands.
Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, People's Republic of China.
Rui
R
Xiong
Xiao-Mei
XM
Cai
Jing
J
Wei
Peng-Yu
PY
Ren
D064127:Aurora Kinases; D001665:Binding Sites; D006860:Hydrogen Bonding / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D013816:Thermodynamics; D013997:Time Factors
D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases