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.

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.

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