Structure-based insights into p38α MAPK: from crystal structures analysis to hit optimization

p38α mitogen-activated protein kinase (MAPK) is a serine/threonine kinase involved in the regulation of pro-inflammatory signaling networks and in the biosynthesis of cytokines, representing a well-recognized therapeutic target for the treatment of autoimmune and inflammatory diseases.1 Over the past two decades, tremendous efforts have been focused on the discovery and development of small-molecule acting as p38α MAPK inhibitors, although no drugs targeting this protein are currently available.2 Thus, the discovery and development of novel small molecule p38α inhibitors represent an exciting area of research. In this context, we have recently identified the pyrazolobenzothiazine core as a new p38αMAPK inhibitor chemoptype.3 Some derivatives showed interesting activity in both p38α MAPK and TNF-α release assays, coupled with a promising kinase selectivity profile. The binding mode prediction of the best hits (Figure 1) has provided clues for further chemical optimization. Towards this aim, first an in depth analysis of the available crystal structures of p38α MAPK in complex with ATP competitive type I inhibitors (TI-Is)4 has been carried out, getting insights into ATP binding site conformations and key inhibitor features. Building on this, we have analysed the impact of protein target conformations on automated molecular docking and docking-based virtual screening. The information gathered from such modelling studies is currently used to aid both our hit-to-lead optimization strategy and the rational identification of new p38a MAPK inhibitor chemotypes through virtual screening campaigns.