p38α MAPK and Type I Inhibitors: Binding Site Analysis and Use of Target Ensembles in Virtual Screening

Molecules

Andrea Astolfi¹  Nunzio Iraci¹  Stefano Sabatini²  Maria Letizia Barreca²  Violetta Cecchetti² 

[1] Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy;

关键词: p38α MAPK;    docking;    virtual screening;    type I inhibitors;   

DOI  :  10.3390/molecules200915842

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.