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

Content Provider	Springer Nature Link
Author	Xiong, Rui Cai, Xiao Mei Wei, Jing Ren, Peng Yu
Copyright Year	2012
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. Figure Binding orientations of Aurora B kinase inhibitors
Starting Page	4591
Ending Page	4601
Page Count	11
File Format	PDF
ISSN	16102940
Journal	Journal of Molecular Modeling
Volume Number	18
Issue Number	10
e-ISSN	09485023
Language	English
Publisher	Springer-Verlag
Publisher Date	2012-05-30
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Aurora B kinase Kinase inhibitor Molecular docking Molecular simulation MM-PBSA Energy decomposition Computer Application in Life Sciences Theoretical and Computational Chemistry Computer Applications in Chemistry Characterization and Evaluation of Materials Molecular Medicine
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Physical and Theoretical Chemistry Computational Theory and Mathematics Catalysis Inorganic Chemistry Computer Science Applications

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