Discovery of potent p38α MAPK inhibitors through a funnel like workflow combining in silico screening and in vitro validation.
Eur J Med Chem
; 182: 111624, 2019 Nov 15.
Article
in En
| MEDLINE
| ID: mdl-31445234
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⯵M. In particular, the 1,4-benzodioxane derivative 5 turned out to be a potent and efficient p38α MAPK inhibitor having IC50â¯=â¯0.07⯵M, 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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Mitogen-Activated Protein Kinase 14
/
Protein Kinase Inhibitors
/
Drug Discovery
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Language:
En
Journal:
Eur J Med Chem
Year:
2019
Type:
Article
Affiliation country:
Italy