A control-validated pan-proteome deep-learning pipeline nominates GPR35 as a candidate target of the orphan bacterial metabolite ligiamycin A
Most microbial natural products with documented bioactivity lack an identified molecular target, which limits their development. We present an open, control-validated computational pipeline for natural-product target hypothesis generation. It combines a pan-proteome deep-learning drug-target interaction (DTI) model (a graph neural-network ligand encoder, an ESM-2 protein language-model encoder, and bidirectional cross-attention) with bias-corrected ranking and control-anchored molecular docking. Applying it to ligiamycin A, a 2022-described Streptomyces/Achromobacter co-culture decalin-amino-maleimide with no reported target, we find that the predicted interactions of the compound are dominated by class-A G-protein-coupled receptors. Using a drug with a known target (losartan) we identify and correct a frequent-hitter bias in the raw model; after correction the standout candidates are uniformly class-A GPCRs, led by the orphan receptor GPR35. Structure-based docking with matched positive and negative controls across three candidates corroborates GPR35 specifically: ligiamycin A scores comparably to the known GPR35 agonist zaprinast at the agonist pocket (-8.1 vs -8.3 kcal/mol; non-binder floor -5.5), whereas FFAR1 is excluded and histamine H2 is inconclusive. We propose GPR35 as a prioritized, experimentally testable target and release the workflow as a reusable tool. The result is a computational hypothesis that requires experimental validation.