Modeling the binding of fused pyrazole inhibitors to p38α MAP kinase using CorrEA-guided ensemble docking

Mitogen-activated protein kinase p38α is an established therapeutic target implicated in inflammatory signaling and a variety of human diseases, including autoimmune disorders, cancer, and neurodegenerative conditions. Fused pyrazoles constitute an important family of ATP-competitive p38α inhibitors, displaying considerable structural diversity and a wide range of inhibitory activities. However, accurately describing inhibitor recognition remains challenging because the ATP-binding site of p38α is inherently flexible and cannot be fully represented by a single receptor conformation. Here, we constructed structural models for a series of 50 fused pyrazole inhibitors, comprising 1 H -pyrazolo[3,4- b ]pyridin-6(7 H )-one (PPO) and 1 H -pyrazolo[3,4- d ]pyridazine (PPz) derivatives, by combining molecular dynamics (MD) simulations, ensemble docking, and the CorrEA methodology. Representative receptor conformations extracted from MD trajectories were used in cross-docking calculations, and the experimental potencies of the series were then supplied to CorrEA as selection criteria to retain, for each inhibitor, a single receptor–ligand complex from among the available docking solutions. The resulting models were examined through ligand pose comparisons, interaction fingerprint analysis, and characterization of conformational changes within the binding site. The ensemble model successfully described all inhibitors while preserving the canonical interaction pattern of ATP-competitive protein kinase inhibitors, revealing that subtle rearrangements of multiple binding-site residues collectively account for the observed differences in inhibitory potency. These findings illustrate how explicit incorporation of receptor flexibility improves the structural interpretation of structure–activity relationships and provide a practical strategy for modeling ligand recognition in flexible protein targets.