p38α MAPK and Type I Inhibitors: Binding Site Analysis and Use of Target Ensembles in Virtual Screening.
Mitogen-activated protein kinase p38α plays an essential role in the regulation of pro-inflammatory signaling, and selective blockade of this kinase could be efficacious in many pathological processes. Despite considerable research efforts focused on the discovery and development of p38α MAPK inhibitors, no drug targeting this protein has been approved for clinical use so far. We herein analyze the available crystal structures of p38α MAPK in complex with ATP competitive type I inhibitors, getting insights into ATP binding site conformation and its influence on automated molecular docking results. The use of target ensembles, rather than single conformations, resulted in a performance improvement in both the ability to reproduce experimental bound conformations and the capability of mining active molecules from compound libraries. The information gathered from this study can be exploited in structure-based drug discovery programs having as the ultimate aim the identification of novel p38α MAPK type I inhibitors.
Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy. andrea.astolfi@chimfarm.unipg.it.
Andrea
A
Astolfi
Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy. nunzio.iraci@gmail.com.
Nunzio
N
Iraci
Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy. stefano.sabatini@unipg.it.
Stefano
S
Sabatini
Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy. lbarreca@unipg.it.
Maria Letizia
ML
Barreca
Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy. violetta.cecchetti@unipg.it.
Violetta
V
Cecchetti
D001665:Binding Sites; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14
docking; p38α MAPK; type I inhibitors; virtual screening