This work describes the rational discovery of novel chemotypes of p38 alpha 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 mu M. In particular, the 1,4-benzodioxane derivative 5 turned out to be a potent and efficient p38 alpha MAPK inhibitor having IC50 = 0.07 mu 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 p38 alpha 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. (C) 2019 Elsevier Masson SAS. All rights reserved.
Discovery of potent p38α MAPK inhibitors through a funnel like workflow combining in silico screening and in vitro validation
Astolfi A.;Manni G.;Manfroni G.;Palazzotti D.;Sabatini S.;Cecchetti F.;Felicetti T.;Cannalire R.;Massari S.;Tabarrini O.;Fallarino F.;Cecchetti V.;Laufer S. A.;Barreca M. L.
2019
Abstract
This work describes the rational discovery of novel chemotypes of p38 alpha 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 mu M. In particular, the 1,4-benzodioxane derivative 5 turned out to be a potent and efficient p38 alpha MAPK inhibitor having IC50 = 0.07 mu 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 p38 alpha 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. (C) 2019 Elsevier Masson SAS. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.