2. Academic Validation
  3. Discovery of potent p38α MAPK inhibitors through a funnel like workflow combining in silico screening and in vitro validation

Discovery of potent p38α MAPK inhibitors through a funnel like workflow combining in silico screening and in vitro validation

  • Eur J Med Chem. 2019 Nov 15:182:111624. doi: 10.1016/j.ejmech.2019.111624.
Andrea Astolfi 1,  Mark Kudolo 2,  Jose Brea 3,  Giorgia Manni 4,  Giuseppe Manfroni 1,  Deborah Palazzotti 1,  Stefano Sabatini 1,  Federica Cecchetti 4,  Tommaso Felicetti 1,  Rolando Cannalire 1,  Serena Massari 1,  Oriana Tabarrini 1,  Maria Isabel Loza 3,  Francesca Fallarino 4,  Violetta Cecchetti 1,  Stefan A Laufer 2,  Maria Letizia Barreca 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, "Department of Excellence 2018-2022", University of Perugia, Via del Liceo 1, 06123, Perugia, Italy.
  • 2 Department of Pharmaceutical & Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls University Tuebingen, Auf der Morgenstelle 8, 72076, Tuebingen, Germany.
  • 3 CIMUS Research Center, University of Santiago de Compostela, Avda de Barcelona s/n, Planta 3, Despacho1, 15782, Santiago de Compostela, Spain.
  • 4 Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06100, Perugia, Italy.
  • 5 Department of Pharmaceutical Sciences, "Department of Excellence 2018-2022", University of Perugia, Via del Liceo 1, 06123, Perugia, Italy. Electronic address: maria.barreca@unipg.it.
PMID: 31445234 DOI: 10.1016/j.ejmech.2019.111624
Abstract

This work describes the rational discovery of novel chemotypes of p38α MAPK inhibitors using a funnel approach consisting of several computer-aided drug discovery methods and biological experiments. Among the identified hits, four compounds belonging to different chemical families showed IC50 values lower than 10 μM. In particular, the 1,4-benzodioxane derivative 5 turned out to be a potent and efficient p38α MAPK inhibitor having IC50 = 0.07 μM, and LEexp and LipE values of 0.38 and 4.8, respectively; noteworthy, the compound had also a promising kinase selectivity profile and the capability to suppress p38α MAPK effects in human immune cells. Overall, the collected findings highlight that the applied strategy has been successful in generating chemical novelty in the inhibitor kinase field, providing suitable chemical candidates for further inhibitor optimization.

Keywords

1,4-Benzodioxane; KNIME; Kinase; Pharmacophore modeling; Virtual screening; p38α MAPK inhibitors.

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