Target-level interpretability and diagnostic framework for molecular docking behavior in antimicrobial resistance...

Molecular docking is widely used to examine ligand interactions with antimicrobial resistance (AMR)-associated proteins, but favorable docking scores do not necessarily indicate mechanistically meaningful binding poses. This study developed a target-level diagnostic framework to determine when structure-based docking outputs are interpretable, conditionally useable, or unsuitable for early-stage AMR research. Eight AMR-relevant targets were evaluated using 30 predefined probe ligands spanning controlled differences in size, polarity, flexibility, and interaction density under a fixed AutoDock Vina protocol. Docking behavior was assessed through crystallographic redocking, reference-anchored pocket localization, PLIP-supported residue-contact analysis, pose classification, and a four-component Composite Interpretability Index applied only within individual targets. Crystallographic redocking showed consistent rank-1 pose reproduction for ErmC, DHFR, and GyrB, whereas AmpC, NDM-1, and VanA showed less stable rank-1 selection despite evidence of recoverable crystallographic poses. Large polar polyphenols and some stress-test ligands frequently produced favorable scores, but score trends were nonmonotonic and target-dependent; favorable scores also occurred in peripheral or out-of-pocket poses, demonstrating partial decoupling between score magnitude and mechanistic localization. At the target level, DHFR and GyrB each produced 29 of 30 highly interpretable probe cases with no gate flags and were classified as docking reliable. AmpC and VanA were classified as docking acceptable, PBP2a, KPC-2, and NDM-1 as docking constrained, and ErmC as unsuitable for generalized heterogeneous-ligand prioritization, with 11 gate flags and the most heterogeneous interpretability profile. The framework therefore provides a conservative pre-deployment gate for determining whether docking should be used routinely, conditionally, or excluded for a given AMR target.