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




p38α MAPK and Type I Inhibitors: Binding Site Analysis and Use of Target Ensembles in Virtual Screening - Download this document for free, or read online. Document in PDF available to download.

Department of Pharmaceutical Sciences, University of Perugia, Via A. Fabretti, 48, 06123 Perugia, Italy



These authors contributed equally to this work.





*

Author to whom correspondence should be addressed.



Academic Editor: Alessandro Pedretti

Abstract 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. View Full-Text

Keywords: p38α MAPK; docking; virtual screening; type I inhibitors p38α MAPK; docking; virtual screening; type I inhibitors





Author: Andrea Astolfi †, Nunzio Iraci †,* , Stefano Sabatini, Maria Letizia Barreca and Violetta Cecchetti

Source: http://mdpi.com/



DOWNLOAD PDF




Related documents