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

Andrea Astolfi; Mark Kudolo; Jose Brea; Giorgia Manni; Giuseppe Manfroni; Deborah Palazzotti; Stefano Sabatini; Federica Cecchetti; Tommaso Felicetti; Rolando Cannalire; Serena Massari; Oriana Tabarrini; Maria Isabel Loza; Francesca Fallarino; Violetta Cecchetti; Stefan A Laufer; Maria Letizia Barreca

doi:10.1016/j.ejmech.2019.111624

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. Epub 2019 Aug 16.

Authors

Andrea Astolfi¹, Mark Kudolo², Jose Brea³, Giorgia Manni⁴, Giuseppe Manfroni¹, Deborah Palazzotti¹, Stefano Sabatini¹, Federica Cecchetti⁴, Tommaso Felicetti¹, Rolando Cannalire¹, Serena Massari¹, Oriana Tabarrini¹, Maria Isabel Loza³, Francesca Fallarino⁴, Violetta Cecchetti¹, Stefan A Laufer², Maria Letizia Barreca⁵

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 LE_exp 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.

MeSH terms

Dose-Response Relationship, Drug
Drug Discovery*
Drug Evaluation, Preclinical
Healthy Volunteers
Humans
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 14 / metabolism
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase 14