Some insights into the binding mechanism of Aurora B kinase gained by molecular dynamics simulation

Abstract

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.

Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach

“…Another hydrogen bond is found between Glu155 and NH group of Acyl-54 at a distance of 3.05 Å. These hydrophilic interactions have been already reported in the literature 73 . As well as docking with the 4AF3 51 structure, the selected compounds were also docked to the active site of other AK-B crystal structures (Table 1 ).…”

“…The most potent compound showed results similar to the reference compound in case of MM(GB/PB)SA method. This might be because of hydrogen bonding to the hinge region which is necessary for the inhibition of kinases 73 . WaterSwap absolute binding free energy calculations for all seven compounds were performed on five representing structures after clustering of 200 ns MD simulation.…”

Polarizable Force Fields for Biomolecular Modeling

“…The values for atomic charges and polarizabilities requires a series of calculations of perturbed ESP maps. This force field has been parameterized for water 25,26 , and for a series of organic molecules including: alkanes, 110 alcohols, 111 aromatics, 112 ethers, 113,114 amides, 109 sulfurs, 115 and ions. 119,120 An attempt has also been made to combine the Drude-based polarizable force field with quantum mechanics in QM/MM methods.…”

Identification of polypharmacological anticancerous molecules against Aurora kinase family of proteins

“…This directly accounts for its higher affinity towards AURK‐B as compared to the other molecules. Previous studies have also reported that the residues Ala157 and Glu161 displayed stable interactions throughout the MD simulations 55 …”

“…Previous studies have also reported that the residues Ala157 and Glu161 displayed stable interactions throughout the MD simulations. 55 The docking interaction between compound 3679 and residues Leu49, Lys53, Lys73, and Ala123 of AURK-C was retained for more than 30% of simulation time (Figure 8A-C). The 5326-AURK-C docked complex revealed the retention of hydrogen bonding interaction with key residues, Ala123, Glu127 but lacked interaction with residues Lys53 and Lys72 (Figure 9A-C).…”