title: Phenylindenone isomers as divergent modulators of p38α MAP kinase.
abstract: Two new fluorophenylindenone derivatives were designed as potential p38α MAPK modulators by preserving the key interactions of the vicinal pyridine/fluorophenyl pharmacophore with the enzyme protein. Interestingly, these two fluorophenylindenone isomers showed divergent activities, with compound 6 behaving as an inhibitor and 5 as a putative activator. These results were rationalized by docking studies and molecular dynamics simulations in terms of stabilization of DFG loop, by compound 5 in a conformation more accessible to phosphorylation.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: andrea.cappelli@unisi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Nannicini
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Chelini
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Paolino
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Germano
authors.initials: G
authors.lastname: Giuliani
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.affiliation: Rottapharm Biotech S.r.l., Via Valosa di Sopra 3, 20900 Monza, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordani
authors.affiliation: Rottapharm Biotech S.r.l., Via Valosa di Sopra 3, 20900 Monza, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sabatini
authors.affiliation: Rottapharm Biotech S.r.l., Via Valosa di Sopra 3, 20900 Monza, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Caselli
authors.affiliation: Rottapharm Biotech S.r.l., Via Valosa di Sopra 3, 20900 Monza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mennuni
authors.affiliation: Rottapharm Biotech S.r.l., Via Valosa di Sopra 3, 20900 Monza, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
authors.affiliation: Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Menziani
mesh_terms: D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006860:Hydrogen Bonding; D007536:Isomerism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010630:Phenindione / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*
chemical_list: D010630:Phenindione; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Docking; Kinases; MAPK; Synthesis