title: Inhibition of cyclin-dependent kinase CDK1 by oxindolimine ligands and corresponding copper and zinc complexes.
abstract: Oxindolimine-copper(II) and zinc(II) complexes that previously have shown to induce apoptosis, with DNA and mitochondria as main targets, exhibit here significant inhibition of kinase CDK1/cyclin B protein. Copper species are more active than the corresponding zinc, and the free ligand shows to be less active, indicating a major influence of coordination in the process, and a further modulation by the coordinated ligand. Molecular docking and classical molecular dynamics provide a better understanding of the effectiveness and kinase inhibition mechanism by these compounds, showing that the metal complex provides a stronger interaction than the free ligand with the ATP-binding site. The metal ion introduces charge in the oxindole species, giving it a more rigid conformation that then becomes more effective in its interactions with the protein active site. Analogous experiments resulted in no significant effect regarding phosphatase inhibition. These results can explain the cytotoxicity of these metal complexes towards different tumor cells, in addition to its capability of binding to DNA, and decreasing membrane potential of mitochondria.
authors.affiliation: Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP, 05508-000, Brazil.
authors.forename: Rodrigo Bernardi
authors.initials: RB
authors.lastname: Miguel
authors.affiliation: Departamento de Física dos Materiais e Mecânica, Instituto de Física, Universidade de São Paulo, Rua do Matão, Travessa R 187, São Paulo, 05508-090, SP, Brazil.
authors.forename: Philippe Alexandre Divina
authors.initials: PA
authors.lastname: Petersen
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-000, SP, Brazil.
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Gonzales-Zubiate
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-000, SP, Brazil.
authors.forename: Carla Columbano
authors.initials: CC
authors.lastname: Oliveira
authors.affiliation: Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP, 05508-000, Brazil.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Departamento de Física dos Materiais e Mecânica, Instituto de Física, Universidade de São Paulo, Rua do Matão, Travessa R 187, São Paulo, 05508-090, SP, Brazil.
authors.forename: Rafael Rodrigues
authors.initials: RR
authors.lastname: do Nascimento
authors.affiliation: Departamento de Física dos Materiais e Mecânica, Instituto de Física, Universidade de São Paulo, Rua do Matão, Travessa R 187, São Paulo, 05508-090, SP, Brazil. hmpetril@if.usp.br.
authors.forename: Helena Maria
authors.initials: HM
authors.lastname: Petrilli
authors.affiliation: Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP, 05508-000, Brazil. amdcferr@iq.usp.br.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: da Costa Ferreira
mesh_terms: D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007097:Imines / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D000078183:Oxindoles; D015032:Zinc / Q000737:chemistry*
chemical_list: D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D007097:Imines; D007211:Indoles; D008024:Ligands; D000078183:Oxindoles; C022960:2-oxindole; D003300:Copper; D018844:Cyclin-Dependent Kinases; D015032:Zinc
keywords: Cytotoxicity mechanism; Kinase inhibitors; Molecular docking; Molecular dynamics; Oxindolimine-metal complexes