title: A Comprehensive Structural Overview of p38α MAPK in Complex with Type I Inhibitors.
abstract: p38α mitogen-activated protein kinase (MAPK) is a well-recognized therapeutic target for the treatment of autoimmune and inflammatory diseases. Over the past two decades, tremendous efforts have been focused on the discovery and development of small-molecule p38α MAPK inhibitors, although currently no drugs targeting this protein are clinically available. Therefore, the identification of novel chemotypes that are able to inhibit p38α MAPK function is still of great therapeutic significance. With the objective to support drug discovery programs aimed at identifying new immunomodulators acting on p38α MAPK, herein we present a complete overview of the available crystal structures of this protein in complex with ATP-site type I inhibitors. The 85 available complexes are classified by chemotype and experimental binding mode, and the ligand-protein interactions are discussed using the most representative inhibitors. The type and frequency of key inhibitor features are analyzed to give a final summary of the chemical requirements of promising p38α MAPK inhibitors. The proposed pharmacophore can be exploited to enhance the opportunities to identify novel type I inhibitors of p38α MAPK.
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti 48, 06123 Perugia (Italy).
authors.forename: Andrea
authors.initials: A
authors.lastname: Astolfi
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti 48, 06123 Perugia (Italy).
authors.forename: Nunzio
authors.initials: N
authors.lastname: Iraci
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti 48, 06123 Perugia (Italy).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti 48, 06123 Perugia (Italy). lbarreca@unipg.it.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti 48, 06123 Perugia (Italy).
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
mesh_terms: D003460:Crystallization; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14
keywords: crystal structures; inhibitors; kinases; ligand-protein interactions; p38α MAPK