title: Sunitinib: from charge-density studies to interaction with proteins.
abstract: Protein kinases are targets for the treatment of a number of diseases. Sunitinib malate is a type I inhibitor of tyrosine kinases and was approved as a drug in 2006. This contribution constitutes the first comprehensive analysis of the crystal structures of sunitinib malate and of complexes of sunitinib with a series of protein kinases. The high-resolution single-crystal X-ray measurement and aspherical atom databank approach served as a basis for reconstruction of the charge-density distribution of sunitinib and its protein complexes. Hirshfeld surface and topological analyses revealed a similar interaction pattern in the sunitinib malate crystal structure to that in the protein binding pockets. Sunitinib forms nine preserved bond paths corresponding to hydrogen bonds and also to the C-H···O and C-H···π contacts common to the VEGRF2, CDK2, G2, KIT and IT kinases. In general, sunitinib interacts with the studied proteins with a similar electrostatic interaction energy and can adjust its conformation to fit the binding pocket in such a way as to enhance the electrostatic interactions, e.g. hydrogen bonds in ligand-kinase complexes. Such behaviour may be responsible for the broad spectrum of action of sunitinib as a kinase inhibitor.
authors.affiliation: Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Maura
authors.initials: M
authors.lastname: Malińska
authors.affiliation: Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Katarzyna N
authors.initials: KN
authors.lastname: Jarzembska
authors.affiliation: Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Goral
authors.affiliation: Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warszawa, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kutner
authors.affiliation: Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Woźniak
authors.affiliation: Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Paulina M
authors.initials: PM
authors.lastname: Dominiak
mesh_terms: D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D055672:Static Electricity; D000077210:Sunitinib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011758:Pyrroles; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D000077210:Sunitinib
keywords: QTAIM; electrostatic potential; interaction energy; protein kinases