title: Targeting aurora2 kinase in oncogenesis: a structural bioinformatics approach to target validation and rational drug design.
abstract: The aurora kinases are a novel oncogenic family of mitotic serine/threonine kinases (S/T kinases) that are overexpressed in a number of solid tumors, including pancreas and colorectal cancer. A PSI-BLAST search [National Center for Biotechnology Information (NCBI)] with the sequence of the S/T kinase domain of human aurora1 kinase [also known as AUR1, ARK2, AIk2, AIM-1, and STK12] and human aurora2 kinase (also known as AUR2, ARK1, AIK, BTAK, and STK15) showed a high sequence similarity to the three-dimensional structures of bovine cAMP-dependent kinase [Brookhaven Protein Data Bank code 1CDK], murine cAMP-dependent kinase (1APM), and Caenorhabditis elegans twitchin kinase (1KOA). When the aurora1 or aurora2 sequence was input into the tertiary structure prediction programs THREADER and 3D-PSSM (three-dimensional position-sensitive scoring matrix), the top structural matches were 1CDK, 1APM, and 1KOA, confirming that these domains are structurally conserved. The structural models of aurora1 and aurora2 were built using 1CDK as the template structure. Molecular dynamics and docking simulations, targeting the ATP binding site of aurora2 with adenylyl imidodiphosphate (AMP-PNP), staurosporine, and six small molecular S/T kinase inhibitors, identified active-site residues that interact with these inhibitors differentially. The docked structures of the aurora2-AMP-PNP and aurora2-staurosporine complexes indicated that the adenine ring of AMP-PNP and the indolocarbazole moiety of staurosporine have similar positions and orientations and provided the basis for the docking of the other S/T kinase inhibitors. Inhibitors with isoquinoline and quinazoline moieties were recognized by aurora2 in which H-89 and 6,7-dimethoxyquinazoline compounds exhibited high binding energies compared with that of staurosporine. The calculated binding energies for the docked small-molecule inhibitors were qualitatively consistent with the IC(50) values generated using an in vitro kinase assay. The aurora2 structural model provides a rational basis for site-directed mutagenesis of the active site; design of novel H-89, staurosporine, and quinazoline analogues; and the screening of the available chemical database for the identification of other novel, small-molecular entities.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Vankayalapati
authors.forename: David J
authors.initials: DJ
authors.lastname: Bearss
authors.forename: José W
authors.initials: JW
authors.lastname: Saldanha
authors.forename: Rubén M
authors.initials: RM
authors.lastname: Muñoz
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Rojanala
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017173:Caenorhabditis elegans / Q000201:enzymology; D029742:Caenorhabditis elegans Proteins; D002148:Calmodulin-Binding Proteins / Q000737:chemistry; D002417:Cattle; D019295:Computational Biology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009124:Muscle Proteins / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D019311:Staurosporine / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D029742:Caenorhabditis elegans Proteins; D002148:Calmodulin-Binding Proteins; D009124:Muscle Proteins; C489233:unc-22 protein, C elegans; C576917:AURKA protein, human; C576921:AURKB protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C491506:air-2 protein, C elegans; D017868:Cyclic AMP-Dependent Protein Kinases; D019311:Staurosporine