Flexible Receptor Docking Provides Structural Models for the Recognition of 2-Amino-heteroaryl-benzothiazole-6-anilide Derivatives by Lck via the CorrEA Method

Abstract Structural models of Lck bound to a chemically diverse series of 62 2-amino-heteroaryl-benzothiazole-6-anilide (AHBA) inhibitors were built to examine how the conformational state of the ATP-binding site shapes the structure-based interpretation of their potency. Docking to the static Lck crystal structure (PDB entry 1QPC) generated plausible complexes for only 54 of the 62 compounds, and produced essentially no relationship between docking scores and experimental pIC50 values, indicating that a single receptor conformation cannot capture how this scaffold is recognized. Receptor flexibility was then introduced through the CorrEA protocol, which cross-docks the series against an ensemble of Lck conformations sampled by molecular dynamics (MD) and, using the measured activities of the series as a reference, selects for each ligand the receptor–pose pair that best accounts for the observed potencies. The resulting ensemble accommodated the entire compound set, overcoming the inability of the rigid receptor to host eight of the derivatives, while preserving the canonical orientation of the AHBA scaffold within the ATP-binding site. The ensemble also recovered the hinge and gatekeeper hydrogen bonds to M319 and T316 expected for ATP-competitive protein kinase (PK) inhibitors, which were only partially satisfied in the rigid-receptor poses. Examination of the selected conformations indicates that the series is accommodated through modest, coordinated rearrangements distributed across the glycine-rich loop, the region beyond the hinge, and the back pocket, rather than through a single dominant conformational change. These models offer an activity-consistent structural framework for interpreting ligand recognition by Lck and a transferable workflow for PKs whose binding sites are conformationally labile.